Preparation of cis-4-O-protected-2-cyclopentenol derivatives

ABSTRACT

The present invention relates to a novel process for preparing cis-4-O-protected-substituted-2-cyclopentenol derivatives comprising, a) dissolving a 4-O-protected-2-cyclopentenone in a suitable organic solvent; and b) treating the solution with a suitable Lewis acid and a suitable reducing agent at a temperature of from about -100° C. to about 20° C. The cis-4-O-protected-substituted-2-cyclopentenol derivatives are useful intermediates in the preparation of various cyclopentanyl and cyclopentenyl purine analogs which are useful as immunosuppressants and in the preparation of various prostaglandins.

This is a division of U.S. patent application Ser. No. 08/588,584, filedFeb. 1, 1996, now U.S. Pat. No. 5,728,899, which is a continuation inpart of U.S. patent application Ser. No. 08/411,136, filed Mar. 27,1995, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to a novel process for preparingcis-4-O-protected-2-cyclopentenol derivatives which are usefulintermediates in the preparation of various cyclopentanyl andcyclopentenyl purine analogs which are useful as immunosuppressants asdisclosed by Borcherding, et al. in European Patent ApplicationPublication Nos. 0 475 411 A1, published Mar. 18, 1992, 0 475 413 A2,published Mar. 18, 1992, and 0 545 413 A1, published Jun. 9, 1993. Inaddition, cis-4-O-protected-2-cyclopentenol derivatives are usefulintermediates in the preparation of various prostaglandins.

SUMMARY OF THE INVENTION

The present invention provides a novel process for the preparation of aCIS compound of the formula (II): ##STR1## wherein Pg is selected fromthe group consisting of benzyl, substituted benzyl, --CH₂ OCH₃, --CH₂SCH₃, --CH₂ OCH₂ phenyl, --CH₂ OCH₂ CH₂ OCH₃, --CH₂ OCH₂ CCl₃, --CH(OCH₂CH₂ Cl)₂ , --CH₂ OCH₂ CH₂ Si(CH₃)₃, --CH(OC₂ H₅)CH₃, --C(OCH₃)(CH₃)₂,--CH(CH₃)OCH(CH₃)₂, --CH₂ CCl₃, --C(CH₃)₃, --CH₂ CH=CH₂, --CH₂CH═CHphenyl, --CH(phenyl)₂, --C(phenyl)₃, tetrahydropyranyl,4-methoxytetrahydropyranyl, 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl,tetrahydrofuranyl, tetrahydrothiofuranyl, and SiR₁ R₂ R₃, wherein R₁, R₂and R₃ are each independently C₁ -C₄ alkyl, phenyl, benzyl, substitutedphenyl or substituted benzyl, comprising;

a) dissolving a compound of the formula (I) ##STR2## wherein Pg isdefined as above, in a suitable organic solvent; and b) treating thesolution with a suitable Lewis acid and a suitable reducing agent at atemperature of from about -100° C. to about 20° C.

The present invention further provides a novel process for thepreparation of the CIS enantiomer of the formula (IIa): ##STR3## whereinPg is selected from the group consisting of benzyl, substituted benzyl,--CH₂ OCH₃, --CH₂ SCH₃, --CH₂ OCH₂ phenyl, --CH₂ OCH₂ CH₂ OCH₃, --CH₂OCH₂ CCl₃, --CH(OCH₂ CH₂ Cl)₂, --CH₂ OCH₂ CH₂ Si(CH₃)₃, --CH(OC₂ H₅)CH₃,--C(OCH₃)(CH₃)₂, --CH(CH₃)OCH(CH₃)₂, --CH₂ CCl₃, --C(CH₃)₃, --CH₂CH=CH₂, --CH₂ CH═CHphenyl, --CH(phenyl)₂, --C(phenyl)₃,tetrahydropyranyl, 4-methoxytetrahydropyranyl, 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl,tetrahydrofuranyl, tetrahydrothiofuranyl, and SiR₁ R₂ R₃, wherein R₁, R₂and R₃ are each independently C₁ -C₄ alkyl, phenyl, benzyl, substitutedphenyl or substituted benzyl, comprising;

a) dissolving an enantiomeric compound of the formula (Ia) ##STR4##wherein Pg is defined as above, in a suitable organic solvent; and b)treating the solution with a suitable Lewis acid and a suitable reducingagent at a temperature of from about -100° C. to about 20° C.

In addition, the present invention provides a novel process for thepreparation of the CIS enantiomer of the formula (IIb): ##STR5## whereinPg is selected from the group consisting of benzyl, substituted benzyl,--CH₂ OCH₃, --CH₂ SCH₃, --CH₂ OCH₂ phenyl, --CH₂ OCH₂ CH₂ OCH₃, --OCH₂OCH₂ CCl₃, --CH(OCH₂ CH₂ Cl)₂, --CH₂ OCH₂ CH₂ Si(CH₃)₃, --CH(OC₂ H₅)CH₃,--C(OCH₃)(CH₃)₂, --CH(CH₃)OCH(CH₃)₂, --CH₂ CCl₃, --C(CH₃)₃, --CH₂CH═CH₂, --CH₂ CH═CHphenyl, --CH(phenyl)₂, --C(phenyl)₃,tetrahydropyranyl, 4-methoxytetrahydropyranyl, 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl,tetrahydrofuranyl, tetrahydrothiofuranyl, and SiR₁ R₂ R₃, wherein R₁, R₂and R₃ are each independently C₁ -C₄ alkyl, phenyl, benzyl, substitutedphenyl or substituted benzyl, comprising;

a) dissolving an enantiomeric compound of the formula (Ib) ##STR6##wherein Pg is defined as above, in a suitable organic solvent; and b)treating the solution with a suitable Lewis acid and a suitable reducingagent at a temperature of from about --100° C. to about 20° C.

In addition, the present invention further provides a novel process forthe preparation of the CIS compounds of the formulas (IIb) and (IV):##STR7## wherein Z is C₂ -C₄ alkanoyl; and Pg is selected from the groupconsisting of benzyl, substituted benzyl, --CH₂ OCH₃, --CH₂ SCH₃, --CH₂OCH₂ phenyl, --CH₂ OCH₂ CH₂ OCH₃, --CH₂ OCH₂ CCl₃, --CH(OCH₂ CH₂ Cl)₂,--CH₂ OCH₂ CH₂ Si(CH₃)₃, --CH(OC₂ H₅)CH₃, --C(OCH₃)(CH₃)₂,--CH(CH₃)OCH(CH₃)₂, --CH₂ CCl₃, --C(CH₃)₃, --CH₂ CH═CH₂, --CH₂CH═CHphenyl, --CH(phenyl)₂, tetrahydropyranyl,4-methoxytetrahydropyranyl, 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl,tetrahydrofuranyl, tetrahydrothiofuranyl, and SiR₁ R₂ R₃, wherein R₁, R₂and R₃ are each independently C₁ -C₄ alkyl, phenyl, benzyl, substitutedphenyl or substituted benzyl, comprising;

a) dissolving a compound of the formula (I) ##STR8## wherein Pg isdefined as above, in a suitable organic solvent; b) treating thesolution with a suitable Lewis acid and a suitable reducing agent at atemperature of from about -100° C. to about 20° C. to yield the CIScompound of formula (II); ##STR9## wherein Pg is as defined above; c)treating the CIS compound of formula (II) with a suitable enzyme and anexcess of a suitable acylating agent, in a suitable solvent to yield amixture of compounds of the formulas (IIb) and (IV), as defined above;and

d) separating the compound of formula (IIb) from compound of formula(IV).

The invention further provides a novel process for the preparation of aCIS compound of formulas (II), (IIa), (IIb) or (IV), as defined above,wherein a suitable alcohol is added to the reaction mixtureconcomitantly with or prior to treating the compound of formula (I) withthe suitable reducing agent.

The invention further provides a novel process for the preparation ofthe CIS compounds of the formulas (VIb) and (VII): ##STR10## wherein Zis C₂ -C₄ alkanoyl; and Pg is selected from the group consisting ofbenzyl, substituted benzyl, --CH₂ OCH₃, --CH₂ SCH₃, --CH₂ OCH₂ phenyl,--CH₂ OCH₂ CH₂ OCH₃, --CH₂ OCH₂ CCl₃, --CH(OCH₂ CH₂ Cl)₂, --CH₂ OCH₂ CH₂Si(CH₃)₃, --CH(OC₂ H₅)CH₃, --C(OCH₃)(CH₃)₂, --CH(CH₃)OCH(CH₃)₂, --CH₂CCl₃, --C(CH₃)₃, --CH₂ CH═CH₂, --CH₂ CH═CHphenyl, --CH(phenyl) ₂,tetrahydropyranyl, 4-methoxytetrahydropyranyl, 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl,tetrahydrofuranyl, tetrahydrothiofuranyl,and SiR₁ R₂ R₃, wherein R₁, R₂and R₃ are each independently C₁ -C₄ alkyl, phenyl, benzyl, substitutedphenyl or substituted benzyl, comprising treating the CIS compound offormula (VI); ##STR11## wherein Pg is as defined above, with a suitableenzyme and an excess of a suitable acylating agent in a suitablesolvent, to yield a mixture of compounds of the formulas (VIb) and(VII), as defined above; and

f) separating the compound of formula (VIb) from the compound of formula(VII).

DETAILED DESCRIPTION OF THE INVENTION

The term "stereoisomers" is a general term for all isomers of individualmolecules that differ only in the orientation of their atoms in space.It includes geometric (cis/trans) isomers, and isomers of compounds withmore than one asymmetric center that are not mirror images of oneanother (diastereomers). The terms "enantiomer" or "enantiomeric" refersto a molecule that is nonsuperimposable on its mirror image and henceoptically active wherein the enantiomer rotates the plane of polarizedlight in one direction and its mirror image rotates the plane ofpolarized light in the opposite direction. The terms "racemic mixture"or "racemic modification" refer to a mixture of equal parts ofenantiomers. A racemic modification or racemic mixture are opticallyinactive. As used herein the prefixes "(+)" and "(-)" are employed todesignate the sign of rotation of plane polarized light by the compound,with (+) meaning the compound is dextrorotatory and (-) meaning thecompound is levorotatory.

The term "enantiomeric enrichment" refers to the increase in the amountof one enantiomer as compared to the other enantiomer. A convenientmethod of expressing enantiomeric enrichment achieved is the concept of"enantiomeric excess" or "ee", which is expressed by the followingequation; ##EQU1## in which E¹ is the amount of the first enantiomer andE² is the amount of the second corresponding enantiomer. For example,where the initial ratio of two enantiomers in a reaction is 50:50 (aracemic mixture) and the reaction produces enantiomeric enrichment witha final ratio of 90:10, then the ee with respect to the first enantiomeris 80%. It is preferred that ee's of greater than 90% be obtained.

It is understood that the enantiomers of formula (IIa) and thecorresponding enantiomers of formula (IIb) are mirror images of eachother. It is further understood that the enantiomers of formulas (IIa)and (IIb) are also in the CIS configuration. In addition, the CIScompounds of formula (II) are racemic mixtures of the correspondingenantiomers of formulas (IIa) and (IIb). It is also further understoodthat the enantiomeric compounds of formula (Ia) and the correspondingenantiomeric compounds of formula (Ib) are mirror images of each other.For example the enantiomer of formula (Ia') and the enantiomer offormula (Ib') below are mirror images of each other. ##STR12##

As used herein the term "C₁ -C₄ alkyl" refers to a saturated straight orbranched chain hydrocarbon radical of one to four carbon atoms. Includedwithin the scope of this term are methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl and the like.

As used herein the term "C₂ -C₄ alkanoyl" refers to an acetyl, propionyland butyryl group.

As used herein the term "C₁ -C₄ alkoxy" refers to a straight or branchedalkoxy group containing from 1-4 carbon atoms and includes methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, and thelike.

As used herein the term "halogen", "halo", "halide", or "hal" refers tofluorine atom, chlorine atom, bromine atom, or iodine atom.

The term "TBDMS" refers to a tert-butyldimethylsilyl functionality ofthe formula: ##STR13##

The term "phenyl" refers the phenyl functionality of the formula:##STR14##

The terms "benzyl" or "Bn" refers the benzyl functionality of theformula: ##STR15##

The term "substituted phenyl" refers the substituted phenylfunctionality of the formula: ##STR16## wherein R is C₁ -C₄ alkyl, C₁-C₄ alkoxy, NO₂, --CN, F, Cl, Br or I, which can be located at theortho, meta or para position on the ring.

The term "substituted benzyl" refers the substituted benzylfunctionality of the formula: ##STR17## wherein R is C₁ -C₄ alkyl, C₁-C₄ alkoxy, NO₂, --CN, F, Cl, Br or I, which can be located at theortho, meta or para position on the ring.

The term "THP" refers the tetrahydro-pyran-2-yl functionality of theformula: ##STR18##

The terms "acetyl", "propionyl" and "butyryl refer the followingfunctional groups respectively: ##STR19##

As used herein a CIS compound such as compound A ##STR20## means thehydrogens at positions 1 and 2 on the cyclopentenyl ring are both on thesame plane of the ring and the substituents OH and OJ, wherein J is H orPg, at positions 1 and 2, are also on the same plane of the ring as eachother. Thus, OH and OJ are in the plane opposite the hydrogens atpositions 1 and 2.

The designation "" refers to a bond that protrudes forward out of theplane of the page.

The designation "" refers to a bond that protrudes backward out of theplane of the page.

The designation "" refers to a bond for which the stereochemistry is notdesignated.

United States patent application Ser. No. 08/411,136 filed Mar. 27,1995, entitled "PREPARATION OF CIS-4-O-PROTECTED-2-CYCLOPENTENOLDERIVATIVES" is hereby incorporated by reference.

Scheme I describes the preparation of compounds of formulas (I), (II)and (III). All the substituents, unless otherwise indicated, arepreviously defined. The reagents and starting materials are readilyavailable to one of ordinary skill in the art. ##STR21##

In step a, the 4-hydroxy-2-cyclopentenone (2) is readily prepared fromfurfuryl alcohol (1) by one of ordinary skill in the art following theprocedure described by Masayoshi Nanni, Harima Ta-machi andMoriyama-shi, Japanese Patent Disclosure Bulletin, KOKAI No. 57-62236,Apr. 15, 1982, or alternatively as described by G, Piancatelli et al.,Tetrahedron, 34, 2775 (1978).

In step b, 4-hydroxy-2-cyclopentenone (2) is protected with a suitableprotecting group to provide the compound of formula (I) utilizingtechniques and procedures well known to one of ordinary skill in theart. Examples of suitable protecting groups are described by T. W.Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons,Inc., 1981, Chapter 2, such as methoxymethyl, methylthiomethyl,benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl,tetrahydrofuranyl, tetrahydrothiofuranyl, l-ethoxyethyl,1-methyl-l-methoxyethyl, 2,2,2-trichloroethyl, tert-butyl, allyl,cinnamyl, p-chlorophenyl, benzyl, p-methoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-chlorobenzyl, p-bromobenzyl, p-cyanobenzyl,diphenylmethyl, triphenylmethyl triethylsilyl, triisopropylsilyl,isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldiethylsilyl,dimethylethylsilyl, methyldiisopropylsilyl, methyl-di-tert-butylsilyl,tribenzylsilyl, triphenylsilyl, phenyldimethylsilyl,benzylmethylethylsilyl, phenylethylmethylsilyl, tri-o-tolylsilyl,tert-butyldiphenylsilyl and the like. The preferred suitable protectinggroups are tetrahydropyranyl and tert-butyldimethylsilyl. The mostpreferred suitable protecting groups are tert-butyldimethylsilyl andtrityl. The compounds of formula (I) are readily prepared by one ofordinary skill utilizing generally the procedures described by T. W.Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons,Inc., 1981, Chapter 2. For example, the protection step can be carriedout by dissolving the 4-hydroxy-2-cyclopentenone (2) in an inert,substantially anhydrous, organic solvent in the presence of an acidacceptor, preferably a nitrogen base such as triethylamine, quinoline,lutidine, imidazole or pyridine. The preferred acid acceptor istriethylamine. Examples of suitable solvents for the protection step aremethylene chloride, tetrahydrofuran, chloroform, tetrachloroethane,nitromethane, benzene, diethyl ether, acetonitrile, dimethylformamideand the like. The preferred suitable solvent is tetrahydrofuran. Acatalytic amount of 4-dimethylaminopyridine (DMAP) may optionally beadded to the solution. The solution is then cooled to about 0° C. andapproximately one equivalent of a suitable silylating agent is added tothe solution. The reaction is allowed to stir for 2 to 14 hours and thenthe compound of formula (I) is isolated and purified by techniques wellknown in the art, such as extractive methods and distillation. Forexample, the reaction is poured into aqueous 0.5N hydrochloric acid andthe phases separated. The aqueous phase is extracted with a suitableorganic solvent, such as heptane. The organic extract is combined withthe organic phase and rinsed with 5% sodium bicarbonate, brine, driedover anhydrous magnesium sulfate, filtered and concentrated undervacuum. The residue can then be purified by Kugelrohr distillation toprovide the compound of formula (I).

In step c, the compound of formula (I) is selectively reduced to providethe CIS compound of formula (II). For example, the compound of formula(I) and a suitable Lewis acid are dissolved in a suitable organicsolvent under an inert atmosphere, such as argon, with stirring. Thesuitable organic solvent is essentially anhydrous and may be a mixtureof suitable organic solvents or a single organic solvent. Examples of asuitable organic solvent are diethyl ether, dipropyl ether, tert-butylmethyl ether, toluene/tert-butyl methyl ether, heptane/tert-butyl methylether, toluene/diethyl ether and the like. The preferred suitableorganic solvents are diethyl ether, toluene/diethyl ether ortoluene/tert-butyl methyl ether. The most preferred suitable organicsolvents are toluene/diethyl ether or toluene/tert-butyl methyl ether.The amount of suitable Lewis acid utilized is from about 0.10 eq toabout 5 eq with about 0.5 eq being preferred. Examples of a suitableLewis acid are lithium chloride, lithium bromide, lithium iodide,lithium perchlorate, zinc chloride, magnesium bromide, cerium(III)chloride and the like. The preferred suitable Lewis acids are lithiumiodide and lithium bromide, with lithium iodide being the most preferredsuitable Lewis acid. The temperature of the solution required for theselective reduction is from about -100° C. to about 20° C. The preferredtemperature is from about -78° C. to about -10° C. with about -25° C.being the most preferred temperature of the solution. The solution isthen treated with a suitable reducing agent. The preferred amount ofsuitable reducing agent utilized is from about 0.4 eq to about 5 eq,with about 0.5 eq being most preferred. Examples of suitable reducingagents are lithium aluminum hydride, lithium trimethoxyaluminumhydride,REDAL® (Aldrich Chemical Company, Milwaukee, Wis.), lithium borohydrideand the like. The preferred suitable reducing agent is lithium aluminumhydride. After addition of the suitable reducing agent, the reaction isstirred for about 1 hour to about 5 hours, with about 2 hours beingpreferred. The reaction is then cautiously quenched and the productisolated and purified utilizing conditions well known in the art. Forexample, approximately 1 to 2 eq of aqueous sodium hydroxide (1N) isadded at a rate that maintains the temperature of the reaction below 20°C. After the reaction is quenched, it is filtered through a pad ofdiatomaceous earth, such as CELITE, (available from Aldrich ChemicalCompany, Milwaukee, Wis.). The pad of diatomaceous earth is then rinsedwith a suitable organic solvent, such as toluene. The filtrate isseparated and the aqueous phase is extracted with a suitable solvent,such as toluene. The organic phases can be combined and washedsequentially with aqueous sodium hydroxide (1N), brine, dried overanhydrous magnesium sulfate, filtered and concentrated under vacuum toprovide the compound of formula (II), which can be purified bytechniques well known in the art, such as chromatography ordistillation. Gas chromatography (GC) can be utilized by one of ordinaryskill in the art to determine the ratio of CIS compound of formula (II)to the by-products of the reduction, which are compounds 2 and 3.

In addition, in step c, the compound of formula (I) can be selectivelyreduced to provide the CIS compound of formula (II) by addition of asuitable alcohol to the reaction mixture described above, underconditions analogous to those described hereinabove, either in thepresence of the suitable Lewis acid, or alternatively, without additionof the suitable Lewis acid. Examples of suitable alcohols areisopropanol, 2-methyl-1-propanol, 2-methyl-2-butanol,2-methyl-1-butanol, 3-methyl-l-butanol, 3-methyl-2-butanol,triethylsilanol, tert-butyldimethylsilanol, methyldiisopropylsilanol,isopropyldimethylsilanol, triisopropylsilanol,methyl-di-tert-butylsilanol, tribenzylsilanol, triphenylsilanol,tert-butyldiphenylsilanol, phenyldimethylsilanol,benzylmethylethylsilanol, phenylmethylethylsilanol, tri-o-tolylsilanol,phenol and the like. The preferred suitable alcohols are isopropanol andtert-butyldimethylsilanol with tert-butyldimethylsilanol being mostpreferred. The amount of alcohol added can range from about 0 mol % toabout 100 mol %. The preferred amount of alcohol added is about 16 mol %to about 30 mol % with about 20 mol % being most preferred. Morespecifically, for example, a suitable reducing agent, such as lithiumaluminum hydride is combined with a suitable Lewis acid, such as lithiumiodide in a suitable organic solvent, such as toluene. The reactionmixture is cooled to about -40° C. to about -20° C. and a mixture of acompound of formula (I), such as4-tert-butyldimethylsiloxy-3-cyclopentanone, tert-butyldimethylsilanoland tert-butyl methyl ether is added slowly to the reaction mixture.After stirring for about 4 hours the reaction is quenched with aqueousammonium chloride and the product isolated and purified by techniqueswell known in the art, such as column chromatography on silica gel or byvacuum distillation.

It is understood by one of ordinary skill in the art that the reagentsmay be combined in various manners so long as the suitable alcohol ispresent when the suitable reducing agent is combined with the compoundof formula (I). For example, the suitable Lewis acid can be combinedwith the suitable reducing agent and suitable alcohol in a suitableorganic solvent, such as toluene. The reaction mixture is then treatedwith a solution of a compound of formula (I) in a suitable organicsolvent, such as tert-butyl methyl ether to provide the CIS compound offormula (II). In another example, the suitable Lewis acid can becombined with the suitable reducing agent, a suitable alcohol in asuitable organic solvent, such as toluene, and a compound of formula (I)followed by addition of a suitable organic solvent, such as tert-butylmethyl ether to provide the CIS compound of formula (II).

In step d, the CIS compound of formula (II) is deprotected underconditions well known in the art to provide the CIS compound of formula(III) see for example T. W. Greene, "Protective Groups in OrganicSynthesis", John Wiley & Sons, Inc., 1981, Chapter 2!. For example, thecompound of formula (II), wherein Pg is a trialkylsilyl protectinggroup, such as a tert-butyldimethylsilyl group, is dissolved in asuitable organic solvent, such as tetrahydrofuran. It is then optionallytreated with approximately 0.15 eq of a suitable amine, such astriethylamine followed by treatment with approximately 1.1 eq oftetrabutylammonium fluoride (as a 1N solution in tetrahydrofuran) atroom temperature. The reaction is stirred for about 2 to 6 hours andthen the product is isolated and purified by techniques well known inthe art. For example, the reaction is concentrated under vacuum and theresidue purified by flash chromatography on silica gel with a suitableeluent, such as 10% acetone/ethyl acetate. The purified material is thenrecrystallized from a suitable organic solvent, such as chloroform toprovide cis-2-cyclopentenyl-1,4-diol of formula (III).

In addition, in step d, the compound of formula (II)

wherein Pg is a tetrahydro-pyran-2-yl group is dissolved in a suitableorganic solvent, such as methanol or ethanol, and treated with asuitable acid, such as pyridinium p-toluenesulfonate (PPTS), at roomtemperature for 1 to 4 hours. The product is isolated and purified bytechniques well known in the art. For example, the reaction isneutralized with a suitable base, such as sodium bicarbonate andconcentrated under vacuum. The residue is then purified by flashchromatography on silica gel with a suitable eluent, such as 10%acetone/ethyl acetate. The purified material is then recrystallized froma suitable organic solvent, such as chloroform to providecis-2-cyclopentenyl-1,4-diol of formula (III).

In a manner analogous to that described in Scheme I, compounds offormulas (IIa) and (IIb) can be prepared from the correspondingcompounds of formulas (Ia) and (lb). The compounds of formulas (Ia) and(Ib) can be prepared by one of ordinary skill in the art, for examplefollowing generally the procedure described by M. Asami, TetrahedronLetters, 26(47), 5803-5806 (1985) or S. P. Khanapure et al., J. Org.Chem., 60, 7548-7551 (1995). In addition, the compounds of formulas (Ia)and (Ib) can be prepared by one of ordinary skill in the art from thecompounds of formulas (IIb) and (IV) prepared in Scheme II shown below.

Scheme II describes the preparation of compounds of formulas (IIb) and(IV) from compounds of formula (II). Compounds of formula (II) can beprepared following the procedure set forth in Scheme I. In addition,compounds of formula (II) can be prepared by converting cyclopentadieneto cis-2-cyclopentenyl-1,4-diol following the procedure described byKaneko, C., et al., Synthesis, 876, (1974), and then monoprotecting thediol with a suitable protecting group under conditions well known to oneof ordinary skill in the art, for example as described by Jain, S., etal., Chemistry and Industry, 17, 576, (September 1990), Rapoport, H. andCastello, A., J. Org. Chem., 51, 1006 (1986), McDougal, P., et al., J.Org. Chem., 51, 3388 (1986) and Roush, et al., J. Org. Chem., 56, 1636(1991). All the substituents, unless otherwise indicated, are previouslydefined. The reagents and starting materials are readily available toone of ordinary skill in the art. ##STR22##

In Scheme II, step A, a compound of formula (II) is subjected to anenzyme catalyzed enantioselective acylation reaction under analogousconditions well known in the art, such as that described by Johnson,C.R., et al., Tetrahedron Letters, 35(12), 1833-1834 (1994), C. R.Johnson and S. J. Bis, Tetrahedron Letters, 33(48), 7287-7290 (1992),Theil, et al., Liebiegs Ann. Chem., 195-200 (1991), Theil, et al.,Tetrahedron, 47(36), 7569-7582 (1991) and Theil, et al., Synthesis, 540(1988), to provide the compounds of formula (IIb) and (IV).

For example, a compound of formula (II) is dissolved in a suitablesolvent or solvent mixture, such as tert-butyl methyl ether, diethylether, diisopropyl ether, tetrahydrofuran, cyclohexane, toluene, hexaneand the like. The preferred suitable solvents are tert-butyl methylether and cyclohexane. The solution is treated with a suitable enzymeand an excess of a suitable acylating agent. Examples of suitableacylating agents are isopropenyl acetate, isopropenyl propionate,isopropenyl butyrate, vinyl acetate, vinyl propionate, vinyl butyrateand the like. The preferred suitable acylating agent is vinyl acetate.About 0.70 equivalents of an alkyl amine, such as triethylamine, may beoptionally added, with stirring, at a temperature of about 15° C. toabout 55° C. A suitable enzyme is an enzyme that catalyzes theenantioselective acylation of the compound of formula (II) wherebyessentially only a single enantiomer of the racemic mixture, such as thecompound of formula (IIa), is acylated under the described conditions toproduce a mixture of compounds of formula (IV) and of formula (IIb),wherein Z is acetyl, propionyl or butyryl. Examples of suitable enzymesare pancreatin (available from Sigma Chemical Company), Candidaantarctica lipase B (Novo Nordisk SP 435), lipozyme IM (available fromNovo Nordisk) and the like. The preferred suitable enzyme is pancreatin.The preferred temperature is 22° C. The reaction is then stirred forabout 6 hours to 24 hours, preferably about 8 hours. The reaction isthen filtered through diatomaceous earth and the filtrate isconcentrated under vacuum to provide a mixture of compounds of formula(IIb) and (IV). The resulting mixture of compounds of formula (IIb) and(IV) are readily separated from one another by techniques and procedureswell known to one of ordinary skill in the art, such as chromatographyor distillation. For example, the mixture can be chromatographed onsilica gel with a suitable eluent, such as ethyl acetate/hexane toprovide a clean separation of compounds of formula (IIb) from compoundsof formula (IV).

In Scheme II, step B, the compounds of formula (IV) can be selectivelyhydrolyzed by procedures well known to one of ordinary skill in the artto produce the compounds of formula (IIa). For example, the compound offormula (IV) wherein Pg is a tetrahydro-pyran-2-yl protecting group, ora trialkylsilyl protecting group, such as a tert-butyldimethylsilylgroup, can be dissolved in a suitable solvent or solvent mixture, suchas THF/methanol/water, and treated with one equivalent of a suitablebase, such as lithium hydroxide monohydrate. The reaction is stirred atroom temperature for about 1 to 8 hours and the product is then isolatedand purified by techniques well known in the art, such as extractivemethods and chromatography. For example, the reaction is diluted with asuitable organic solvent, such as diethyl ether, rinsed with water,dried over anhydrous magnesium sulfate, filtered and concentrated undervacuum. The residue is then purified by chromatography on silica gelwith a suitable eluent, such as ethyl acetate/hexane, to provide thecompound of formula (IIa).

In Scheme II, step C, the compounds of formula (IV) can be selectivelyhydrolyzed by procedures well known to one of ordinary skill in the artto produce compounds of formula (V). For example, the compound offormula (IV) wherein Pg is a tetrahydro-pyran-2-yl protecting group canbe dissolved in a suitable organic solvent such as ethanol, and treatedwith p-toluenesulfonic acid. In addition, the compound wherein Pg is atert-butyldimethylsilyl group on formula (IV), can be dissolved in asuitable organic solvent, such as tetrahydrofuran, and treated withn-tetrabutylammonium fluoride. Either reaction is then stirred at roomtemperature for about 1 to 8 hours and the product is then isolated andpurified by techniques well known in the art, such as extractive methodsand chromatography. For example, either reaction is diluted with asuitable organic solvent, such as diethyl ether, rinsed with water,dried over anhydrous magnesium sulfate, filtered and concentrated undervacuum. The residue is then purified by chromatography on silica gelwith a suitable eluent, such as ethyl acetate/hexane, to provide thecompound of formula (V).

The compounds of formulas (IIb) and (IIa) can then be readily convertedto the corresponding enantiomers of O-protected4-hydroxy-2-cyclopentenone by procedures known to one of ordinary skillin the art. For example, the procedures described by M. Asami,Tetrahedron Letters, 26(47), 5803-5806 (1985), K. Laumen and MSchneider, Tetrahedron Letters, 25(51), 5875-5878 (1984), M. Nara, etal., Tetrahedron, 36, 3161-3170 (1980) and J. Nokami, et al.,Tetrahedron Letters, 32(21), 2409-2412 (1991), can be followed in ananalogous manner to produce both enantiomers ofO-protected-4-hydroxy-2-cyclopentenone. For example, the compound offormulas (IIa) or (IIb) is dissolved in a suitable organic solvent, suchas methylene chloride and treated with a suitable oxidizing agent, suchas manganese dioxide (MnO₂), pyridinium dichromate (PDC) or pyridiniumchlorochromate (PCC) to provide the ketones of formulas (Ia) and (Ib).The compounds of formulas (IIa) and (IIb) are useful syntheticintermediates for the enantioselective synthesis of prostaglandins, forexample see M. Asami, Tetrahedron Letters, 26(47), 5803-5806 (1985). Inaddition, the enantiomers of formulas (Ia) and (Ib) can be prepared ingeneral following the procedure of Corey, E. J., et al., TetrahedronLetters, 27, 2199 (1986) or S. P. Khanapure et al., J. Org. Chem., 60,7548-7551 (1995).

Compounds of the formulas (VIa), (VIb), (VII) and (VIII) can be preparedas described in Scheme III. All the substituents, unless otherwiseindicated, are previously defined. The reagents and starting materialsare readily available to one of ordinary skill in the art. ##STR23##

In Scheme III the compound of formula (VI) is prepared by one ofordinary skill in the art, for example, by reduction of the double bondin the compound of formula (II). More specifically, the compound offormula (II) is combined with Ni₂ B in a suitable organic solvent, suchas methanol and the reaction mixture is stirred for about 15-20 hours atroom temperature under an atmosphere of hydrogen. The product is thenisolated and purified by techniques and procedures well known in theart. For example, the hydrogen atmosphere is purged with nitrogen, thereaction mixture is filtered through diatomaceous earth, the solidswashed with methanol and the filtrate concentrated under vacuum. Theresidue can then be purified by column chromatography or vacuumdistillation to provide the purified compound of formula (VI).

In Scheme III, step A, the compound of formula (VI) is subjected to anenzyme catalyzed enantioselective acylation reaction under analogousconditions well known in the art, such as that described by Johnson, C.R., et al., Tetrahedron Letters, 35(12), 1833-1834 (1994), C. R. Johnsonand S. J. Bis, Tetrahedron Letters, 33(48), 7287-7290 (1992), Theil, etal., Liebiegs Ann. Chem., 195-200 (1991), Theil, et al., Tetrahedron,47(36), 7569-7582 (1991) and Theil, et al., Synthesis, 540 (1988), toprovide the compounds of formula (VIb) and (VII).

For example, a compound of formula (VI) is dissolved in a suitablesolvent or solvent mixture, such as tert-butyl methyl ether, diethylether, diisopropyl ether, tetrahydrofuran, cyclohexane, toluene, hexaneand the like. The preferred suitable solvents are tert-butyl methylether and cyclohexane. The solution is treated with a suitable enzymeand an excess of a suitable acylating agent. Examples of suitableacylating agents are isopropenyl acetate, isopropenyl propionate,isopropenyl butyrate, vinyl acetate, vinyl propionate, vinyl butyrateand the like. The preferred suitable acylating agent is vinyl acetate.About 0.70 equivalents of an alkyl amine, such as triethylamine, may beoptionally added, with stirring, at a temperature of about 15° C. toabout 55° C. The preferred temperature is about 22° C. A suitable enzymeis an enzyme that catalyzes the enantioselective acylation of thecompound of formula (VI) whereby essentially only a single enantiomer ofthe racemic mixture, such as the compound of formula (VIa), is acylatedunder the described conditions to produce a mixture of compounds offormula (VII) and of formula (VIb), wherein Z is acetyl, propionyl orbutyryl. Examples of suitable enzymes are pancreatin (available fromSigma Chemical Company), Candida antarctica lipase B (Novo Nordisk SP435), lipozyme IM (available from Novo Nordisk) and the like. Thepreferred suitable enzyme is pancreatin. The reaction is then stirredfor about 6 hours to about 30 hours, preferably about 8 hours. Thereaction is then filtered through diatomaceous earth and the filtrate isconcentrated under vacuum to provide a mixture of compounds of formula(VIb) and (VII). The resulting mixture of compounds of formula (VIb) and(VII) are readily separated from one another by techniques andprocedures well known to one of ordinary skill in the art, such aschromatography or distillation. For example, the mixture can bechromatographed on silica gel with a suitable eluent, such as ethylacetate/hexane to provide a clean separation of compounds of formula(VIb) from compounds of formula (VII).

In Scheme III, step B, the compounds of formula (VII) can be selectivelyhydrolyzed by procedures well known to one of ordinary skill in the artto produce the compounds of formula (VIa). For example, the compound offormula (VII) wherein Pg is a tetrahydro-pyran-2-yl protecting group, ora trialkylsilyl protecting group, such as a tert-butyldimethylsilylgroup, can be dissolved in a suitable solvent or solvent mixture, suchas THF/methanol/water, and treated with one equivalent of a suitablebase, such as lithium hydroxide monohydrate. The reaction is stirred atroom temperature for about 1 to 8 hours and the product is then isolatedand purified by techniques well known in the art, such as extractivemethods and chromatography. For example, the reaction is diluted with asuitable organic solvent, such as diethyl ether, rinsed with water,dried over anhydrous magnesium sulfate, filtered and concentrated undervacuum. The residue is then purified by chromatography on silica gelwith a suitable eluent, such as ethyl acetate/hexane, to provide thecompound of formula (VIa).

In Scheme III, step C, the compounds of formula (VII) can be selectivelyhydrolyzed by procedures well known to one of ordinary skill in the artto produce compounds of formula (VIII). For example, the compound offormula (VII) wherein Pg is a tetrahydro-pyran-2-yl protecting group canbe dissolved in a suitable organic solvent such as ethanol, and treatedwith p-toluenesulfonic acid. In addition, the compound wherein Pg is atert-butyldimethylsilyl group on formula (IV), can be dissolved in asuitable organic solvent, such as tetrahydrofuran, and treated withn-tetrabutylamonium fluoride. Either of the above reaction mixtures isthen stirred at room temperature for about 1 to 8 hours and the productis then isolated and purified by techniques well known in the art, suchas extractive methods and chromatography. For example, either of theabove reaction mixtures is diluted with a suitable organic solvent, suchas diethyl ether, rinsed with water, dried over anhydrous magnesiumsulfate, filtered and concentrated under vacuum. The residue is thenpurified by chromatography on silica gel with a suitable eluent, such asethyl acetate/hexane, to provide the compound of formula (VIII).

The compounds of formulas (VIb) and (VIa) can then be readily convertedto the corresponding enantiomers of O-protected 3-hydroxycyclopentanoneby procedures known to one of ordinary skill in the art. For example,the compound of formulas (VIa) or (VIb) is dissolved in a suitableorganic solvent, such as methylene chloride and treated with a suitableoxidizing agent, such as pyridinium dichromate (PDC), pyridiniumchlorochromate (PCC) or Swern conditions to provide the correspondingketones.

The following examples present typical syntheses as described in SchemesI, II and III. These examples are understood to be illustrative only andare not intended to limit the scope of the present invention in any way.

Gas chromatography retention times reported herein are obtained underthe following conditions; a Hewlett Packard 5890 Series II GasChromatograph is utilized, with a 30 m×0.32 mm HP-5 cross-linked, 5% PHME silicone column fitted thereto. The flow rate is set at 30 mL/minwith helium as the carrier gas. The injection port temperature is 200°C., the detector temperature is 275° C. and the program used is agradient wherein the initial temperature is set at 100° C. for 10minutes and then it is increased at a rate of 10° C./minute to 200° C.where it is held for 5 minutes prior to terminating.

In addition, chiral chromatography is readily utilized by one ofordinary skill in the art to determine the ee of a particular compound.For example, a CDX-β 10 m×0.25 mm id (available from J & W Scientific,Folsom, Calif.) can be utilized under standard conditions, such as acolumn temperature of 100° C., injector temperature of 200° C. anddetector temperature of 220° C. Alternatively, the ee of a particularcompound can be determined by preparing the corresponding Mosher'sEsters of the compounds from(R)-(+)-α-methoxy-α-(trifluoromethyl)phenylacetic acid or(S)-(-)-α-methoxy-α-(trifluoromethyl)phenylacetic acid utilizingtechniques well known to one of ordinary skill in the art, for examplesee Dale, J. A., Dull, D. L. and Mosher, H. S, J. Org. Chem., 34(9),2543-2549 (1969). The amounts of each resulting diastereomer can bedetermined by ¹⁹ F NMR or separation by column chromatography, chiralcolumn chromatography or gas chromatography, as is well known in theart, thereby allowing calculation of the ee of the compound.

As used herein, the following terms have the indicated meanings: "g"refers to grams; "mmol" refers to millimoles; "ml" refers tomilliliters; "bp" refers to boiling point; "mp" refers to melting point;"° C." refers to degrees Celsius; "mmHg" refers to millimeters ofmercury; "μL"refers to microliters; "μg" refers to micrograms; and"μM"refers to micromolar; "R_(f) " refers to retention factor; "δ"refers to parts per million downfield from tetramethylsilane; " α!_(D)²⁰ " refers to specific rotation of the D line of sodium at 20° C.obtained in a 1 decimeter cell; "c" refers to concentration in g/mL;"DMF" means dimethylformamide; "THF" means tetrahydrofuran; "TBME" meanstert-butyl methyl ether; "NMM" means N-methylmorpholine; "DMSO" meansdimethylsulfoxide; and "DMAP" means 4-dimethylaminopyridine.

EXAMPLE 1

Preparation of 4-hydroxy-2-cyclopentenone ##STR24##

Scheme I, step a; A solution of furfuryl alcohol (125 g, 1.27 mol) inwater (3.7 L) is treated with KH₂ PO₄ (6.3 g, 46.3 mmol). The pH of thesolution is adjusted to pH 4.1 (pH meter) with H₃ PO₄ and then heated to99° C. under an atmosphere of nitrogen for 40 hours. The solution isthen cooled and washed with methylene chloride (2×500 mL). The organiclayers are combined and extracted with water (2 ×500 mL). The aqueouslayer and aqueous extracts are combined and concentrated under vacuum(70° C., 20 mm Hg) to provide an oil. The oil is dissolved in methylenechloride (1 L), dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum to provide the title compound (66 g, 53%) as adark oil; ¹ H NMR (CDCl₃) δ 7.61 (dd, J=5.6, 4.8 Hz, 1H), 6.20 (dd,J=5.6, 4.8 Hz, 1 H), 5.01-5.04 (m, 1H), 3.61 (bs, 1H), 2.75 (dd, J=18.5,3.2 Hz, 1H), 2.26 (dd, J=18.5, 6.0 Hz, 1H); ¹³ C NMR (CDCl₃) δ 207.4,164.0, 134.7, 70.1, 44.1; IR (neat) ν_(max) 3387, 2974, 1711 cm⁻¹ ; MS(EI) m/e (% relative intensity) 98 (M⁺, 100).

Anal. Calcd for C₅ H₆ O₂ ·O.16H₂ O: C, 59.47; H, 6.30, H₂ O, 2.9; Found:C, 59.56; H, 6.52, H₂ O, 3.0.

EXAMPLE 2

Preparation of 4-tert-butyldimethylsiloxy-2-cyclopentenone. ##STR25##

Scheme I, step b; A solution of 4-hydroxy-2-cyclopentenone (191 g, 1.95mol, prepared in example 1) and triethylamine (430 mL, 3.09 mol) inanhydrous tetrahydrofuran (1 L) is treated with 4-dimethylaminopyridine(4.90 g, 40.0 mmol). The solution is cooled to 0° C. and treatedportionwise, over 10 minutes, with tert-butyldimethylsilyl chloride (278g, 1.84 mol) maintaining the temperature at or below 10° C. The reactionis then allowed to stir overnight at room temperature. It is then pouredinto aqueous HCl (0.5N, 1 L). The phases are separated and the aqueousphase is extracted with heptane (2×1 L). The organic phase and organicextracts are combined, washed with aqueous HCl (0.5N, 2×500 mL), then 5%sodium bicarbonate (500 mL), then brine (500 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated under vacuum (40° C., 20mmHg) to provide the title compound (325 g). This is purified byKugelrohr distillation (70°-80° C., 1 mmHg) to provide the titlecompound (282 g, 72% yield) as a light yellow oil, R_(f) =0.55, 20%ethyl acetate/hexane, GC retention time is 14.97 minutes; ¹ H NMR(CDCl₃) δ 7.48 (dd, J=5.7, 2.4 Hz, 1 H), 6.20 (d, J=5.7 Hz, 1 H),4.95-4.99 (m, 1 H), 2.72 (dd, J=18.2, 6.0 Hz, 1 H), 2.25 (dd, J=18.2,2.3 Hz, 1 H), 0.88 (s, 9 H), 0.11 (s, 6 H); ¹³ C NMR (CDCl₃) δ 206.4,163.8, 134.4, 70.8, 44.9, 25.7, 25.6, 18.0; IR (neat) ν_(max) 2957,2931, 2887, 2858, 1725 cm⁻ ¹ ; MS (EI) m/e (% relative intensity) 212(M⁺, 5), 155 (M⁺ -57, 100).

Anal. Calcd for C₁₁ H₂₀ O₂ Si: C, 62.21; H, 9.51; Found: C, 62.39; H,9.50.

EXAMPLE 3a

Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol.##STR26##

Scheme I, step c; A mechanically stirred solution of4-tert-butyldimethylsiloxy-2-cyclopentenone (50.2 g, 236 mmol) inanhydrous toluene (1 L) under an atmosphere of argon is treated withlithium iodide (160 g, 1.20 mol). The mixture is cooled to -20° C. andtreated with lithium aluminum hydride (9.0 g, 237 mmol) in one portion.The reaction is then stirred for 5 minutes and anhydrous tert-butylmethyl ether (200 mL) is added at a rate that maintains the temperatureof the reaction at or below -15° C. (total addition time isapproximately 3 minutes). The reaction is stirred for one hour at -20°C. and then it is quenched by slow addition of aqueous sodium hydroxide(1N, 250 mL) at a rate that maintains the temperature of the reactionbelow 20° C. The resulting suspension is then filtered through a pad ofdiatomaceous earth and the pad is subsequently rinsed with toluene (400mL). The filtrate phases are separated and the aqueous phase isextracted with toluene (300 mL). The organic phase and organic extractare combined, rinsed with aqueous sodium hydroxide (1N, 300 mL), brine(300 mL), dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum (40° C., 20 mmHg). The residue is thenpurified by Kugelrohr distillation (60°-80° C., 1 mmHg) to provide thetitle compound (37.4 g, 74% yield) as a colorless oil; cis/trans/l-2+l-4addition, 95.3/2.1/2.6; R_(f) =0.20, 20% ethyl acetate/hexane, GCretention time for the title compound is 13.95 minutes, while CCretention times for the byproducts corresponding to compounds 3 (trans)and 4 (l-2+l-4 addition) in Scheme I wherein Pg is a TBDMS group are14.45 min. and 14.06 min. respectively; for the title compound, ¹ H NMR(CDCl₃) δ 5.93 (dt, J=5.5, 1.7 Hz, 1 H), 5.84 (dt, J=5.5, 1.6 Hz, 1 H),4.63-4.68 (m, 1 H), 4.52-4.62 (m, 1 H), 2.76-2.86 (bs, 1 H), 2.69 (dt,J=13.8, 7.1 Hz, 1 H), 1.52 (dt, J=13.8, 4.7 Hz, 1 H), 0.90 (s, 9 H),0.09 (s, 6 H); ¹³ C NMR (CDCl₃) δ 136.7, 135.6, 75.1, 75.0, 44.5, 25.9,18.1; IR (neat) ν_(max) 3373, 2957, 2932 cm⁻¹ ; MS (EI) m/e (% relativeintensity) 157 (M⁺ -57).

EXAMPLE 3b

Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol.

Scheme I, step c; A mechanically stirred solution of4-tert-butyldimethylsiloxy-2-cyclopentenone (175 g, 824 mmol) inanhydrous toluene (1.5 L) under an atmosphere of argon is treated withlithium iodide (240 g, 1.79 mol). The mixture is cooled to -20° C. andtreated with lithium aluminum hydride (13.5 g, 356 mmol) in one portion.The reaction is then stirred for 5 minutes and anhydrous tert-butylmethyl ether (300 mL) is added at a rate that maintains the temperatureof the reaction at or below -15° C. (total addition time isapproximately 3 minutes). The reaction is stirred for 3 hours at -20° C.and then it is quenched by slow addition of aqueous sodium hydroxide(1N, 250 mL) at a rate that maintains the temperature of the reactionbelow 20° C. The resulting suspension is then filtered through a pad ofdiatomaceous earth and the pad is subsequently rinsed with toluene (400mL). The filtrate phases are separated and the aqueous phase isextracted with toluene (450 mL). The organic phase and organic extractare combined, rinsed with aqueous sodium hydroxide (1N, 450 mL), brine(450 mL), dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum (40° C., 20 mmHg). The residue is thenpurified by Kugelrohr distillation (60°-80° C., 1 mmHg) to provide thetitle compound (120 g, 68% yield) as a colorless oil; cis/trans/l-2+l-4addition, 92/4/4.

EXAMPLE 3c

Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol.

Scheme I, step c; A mechanically stirred solution of4-tert-butyldimethylsiloxy-2-cyclopentenone (1.01 g, 4.76 mmol) inanhydrous ethyl ether (20 mL) under an atmosphere of argon is treatedwith lithium iodide (3.20 g, 23.9 mmol). The mixture is cooled to -78°C. and treated with lithium aluminum hydride (184 mg, 4.85 mmol) in oneportion. The reaction is then stirred for 90 minutes. It is thenquenched by slow addition of aqueous sodium hydroxide (1N, 23 mL) at arate that maintains the temperature of the reaction below 20° C. Theresulting suspension is then filtered through a pad of diatomaceousearth and the pad is subsequently rinsed with ether. The filtrate phasesare separated and the aqueous phase is extracted with ether (20 mL). Theorganic phase and organic extract are combined, rinsed with aqueoussodium hydroxide (1N, 20 mL), brine (20 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated under vacuum (40° C., 20mmHg). The residue is then purified by Kugelrohr distillation (60°-80°C., 1 mmHg) to provide the title compound (820 mg, 80% yield) as acolorless oil; cis/trans/l-2+l-4 addition, 88.5/3.3/8.2.

EXAMPLE 3d

Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol.

Scheme I, step c; A mechanically stirred solution of4-tert-butyldimethylsiloxy-2-cyclopentenone (501 mg, 2.36 mmol) inanhydrous toluene (10 mL) under an atmosphere of argon is treated withlithium bromide (1.06 g, 12.2 mmol). The mixture is cooled to -20° C.with an ice/salt bath and treated with lithium aluminum hydride (92.0mg, 2.42 mmol) in one portion followed by tert-butyl methyl ether (1.0mL). The ice/salt bath is replaced with an ice bath and the reaction isthen stirred for 2 hours at 0° C. It is then quenched by slow additionof aqueous sodium hydroxide (1N, 7.0 mL) at a rate that maintains thetemperature of the reaction below 20° C. The resulting suspension isthen filtered through a pad of diatomaceous earth and the pad issubsequently rinsed with toluene. The filtrate phases are separated andthe aqueous phase is extracted with toluene. The organic phase andorganic extract are combined, rinsed with aqueous sodium hydroxide (1N),brine, dried over anhydrous magnesium sulfate, filtered and concentratedunder vacuum (40° C., 20 mmHg). The residue is then purified byKugelrohr distillation (60°-80° C., 1 mmHg) to provide the titlecompound (350 mg, 69% yield) as a colorless oil; cis/trans/l-2+l-4addition, 92.7/6.3/1.0.

EXAMPLE 3e

Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol.

Scheme I, step c; A stirred solution of ZnCl₂ (19 mL, 19 mmol, 1M inether) is treated with 4-tert-butyldimethylsiloxy-2-cyclopentenone (2.0g, 9.42 mmol) under an atmosphere of argon. The solution is cooled to-20° C. and treated dropwise with lithium aluminum hydride (9.0 mL, 9.0mmol, 1M in ether) at such a rate as to keep the reaction temperature ator below -15° C. After stirring for about 2 hours at -20° C.,approximately 5 mL of 1N NaOH was added. The reaction is filteredthrough diatomaceous earth, dried over anhydrous magnesium sulfate,filtered and concentrated under vacuum to provide the title compound(1.3 g); cis/trans/l-2+l-4 addition, 81/3/16.

EXAMPLE 3f

Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol.

Scheme I, step c; A stirred solution of4-tert-butyldimethylsiloxy-2-cyclopentenone (2.0 g, 9.42 mmol) inanhydrous toluene (15 mL) under an atmosphere of argon is treated withMgBr₂ (3.5 g, 19.0 mol). The mixture is cooled to -25° C. and treatedwith lithium aluminum hydride (178 mg, 4.69 mmol) in one portion,followed by addition of anhydrous tert-butyl methyl ether (3.0 mL). Thereaction is stirred at -20° C. for 2 hours and then overnight at roomtemperature. Additional lithium aluminum hydride (178 mg, 4.69 mmol) isadded at room temperature and the reaction is stirred for 2 hours. Thereaction is then quenched by slow addition of 1N NaOH (5 mL) followed byfiltration through diatomaceous earth. The filtrate is dried overanhydrous magnesium sulfate, filtered and concentrated under vacuum toprovide the title compound (1.3 g); cis/trans/l-2+l-4 addition, 90/3/7.

EXAMPLE 3q

Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol with 2.8mol % tert-butyldimethylsilanol added to the reaction mixture.

Scheme I, step c; Into a 100 mL flask equipped with a mechanicalstirrer, a low temperature thermometer and a 60 mL addition funneltopped with a nitrogen bubbler is placed lithium aluminum hydride (0.5g, 0.013 mol), lithium iodide (6.7 g, 0.05 mol) and toluene (34 g). Theslurry is cooled to -40° C. and the addition funnel is charged with4-tert-butyldimethylsiloxy-3-cyclopentanone (5.0 g, 0.024 mol,containing 2.8% tert-butyldimethylsilanol as determined by gaschromatography on a Hewlett-Packard 5890 Series II gas chromatograph, aHewlett-Packard integrator, a Hewlett-Packard column, PH-1, 10 m, 0.53mm ID, 2.56 μm, injection port at 190° C., detector at 270° C., using agradient with a starting temperature of 50° C. for 2 minutes thenincreasing at a rate of 20° C./minute to 250° C. for 5 minutes) andtert-butylmethyl ether (18 g, TBME). The cyclopentenone/TBME solution isadded to the slurry over 5 minutes at such a rate as to maintain theinternal reaction temperature between -30° C. and -36° C. The reactionmixture is then allowed to warm to -30° C. and stir for 4 hours. Thereaction is quenched by slow addition of a 5 wt % solution of aqueousammonium chloride (20 g). Toluene (20 g) is added and the phases areseparated. The aqueous phase is then extracted with toluene (30 g). Theorganic phases are combined, washed with water (30 g), dried overanhydrous magnesium sulfate, filtered and concentrated under vacuum. Theresidue is purified by vacuum distillation through a 14 cm, packed glassbead (4 mm) column at 0.2 mmHg (63°-66° C.) to provide the titlecompound (3.9 g, 77%); cis/trans/l-2+l-4 addition, 95/4/1.

EXAMPLE 3h

Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol with 16mol % tert-butyldimethylsilanol added to the reaction mixture.

Scheme I, step c; Into a 100 mL flask equipped with a mechanicalstirrer, a low temperature thermometer and a 60 mL addition funneltopped with a nitrogen bubbler is placed lithium aluminum hydride (0.5g, 0.013 mol), lithium iodide (6.7 g, 0.05 mol) and toluene (34 g). Theslurry is cooled to -30° C. and the addition funnel is charged with4-tert-butyldimethylsiloxy-3-cyclopentanone (4.3 g, 0.02 mol, containing2.8% tert-butyldimethylsilanol as determined in example 3 g),tert-butyldimethylsilanol (0.6 g, 0.005 mol) and tert-butylmethyl ether(18 g, TBME). The additional tert-butyldimethylsilanol is added toadjust the solution to contain 16% tert-butyldimethylsilanol. Thecyclopentenone/silanol/TBME solution is added in one portion resultingin an 8° C. exotherm. The reaction mixture is cooled and maintained atbetween -28° C. and -32° C. for 1.5 hours. The reaction is then quenchedby slow addition of a 5 wt % solution of aqueous ammonium chloride (20g) and the phases are separated. The aqueous phase is extracted withmethylene chloride (2×20 g). The organic phases are combined, washedwith water (20 g), dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum. The residue is purified by vacuumdistillation through a 14 cm packed glass bead (4 mm) column at 0.5 mmHg(67°-70° C.) to provide the title compound (3.5 g, 81%);cis/trans/l-2+l-4 addition, 96.3/2.8/0.9.

EXAMPLE 3I

Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol with 17mol % tert-butyldimethylsilanol added to the reaction mixture.

Scheme I, step c; Into a 100 mL flask equipped with a mechanicalstirrer, a low temperature thermometer and a 60 mL addition funneltopped with a nitrogen bubbler is placed lithium aluminum hydride (0.5g, 0.013 mol), lithium iodide (1.4 g, 0.010 mol) and toluene (34 g). Theslurry is cooled to -33° C. and the addition funnel is charged with4-tert-butyldimethylsiloxy-3-cyclopentanone (4.3 g, 0.02 mol, containing2.8% tert-butyldimethylsilanol as determined in example 3 g),tert-butyldimethylsilanol (0.6 g, 0.005 mol) and tert-butylmethyl ether(18 g, TBME). The additional tert-butyldimethylsilanol is added toadjust the solution to contain 17% tert-butyldimethylsilanol. Thecyclopentenone/silanol/TBME solution is added in one portion resultingin an internal temperature of -23° C. The reaction mixture temperatureis maintained near -30° C. for 23 hours and it is then quenched with 5wt % aqueous ammonium chloride (21 g). The phases are separated and theaqueous phase is extracted with toluene (2×20 g). The organic phases arecombined, washed with water (25 g), dried over anhydrous magnesiumsulfate, filtered and concentrated under vacuum. The residue is purifiedby vacuum distillation through a 14 cm packed glass bead (4 mm) columnat 0.4 mmHg (65°-68° C.) to provide the title compound (3.2 g, 74%);cis/trans/l-2+l-4 addition, 96.2/2.8/1.

EXAMPLE 3J

Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol with 18mol % tert-butyldimethylsilanol added to the reaction mixture.

Scheme I, step c; Into a 100 mL flask equipped with a mechanicalstirrer, a low temperature thermometer and a 60 mL addition funneltopped with a nitrogen bubbler is placed lithium aluminum hydride (0.5g, 0.013 mol) and toluene (30 g). The slurry is cooled to -30° C. andthe addition funnel is charged with tert-butyldimethylsilanol (0.6 g,0.005 mol) and toluene (9 g). The silanol/toluene solution is added inone portion resulting in mild gas evolution. The additionaltert-butyldimethylsilanol is added to adjust the solution to contain 18%tert-butyldimethylsilanol. The mixture is stirred at a temperature ofbetween -25° C. and -30° C. for 15 minutes. The addition funnel ischarged with 4-tert-butyldimethylsiloxy-3-cyclopentanone (4.3 g, 0.02mol, containing 2.8% tert-butyldimethylsilanol as determined in example3 g) and tert-butyl methyl ether (13 g, TBME). The cyclopentenone/TBMEsolution is added in one portion to the slurry resulting in a 9° C.exotherm (-21° C. internal reaction temperature). The reaction mixturetemperature is maintained near -25° C. for 1.5 hours and then thereaction is quenched with 5 wt % aqueous ammonium chloride. Toluene (20g) is added and the phases are separated. The aqueous phase is extractedwith toluene (30 g). The organic phases are combined, washed with water(30 g), dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum. The residue is purified by vacuumdistillation through a 14 cm packed glass bead (4 mm) column at 0.5 mmHg(67°-69° C.) to provide the title compound (3.1 g, 72%);cis/trans/l-2+l-4 addition, 95/3.9/1.1.

EXAMPLE 3K

Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol with 20mol % isopropanol added to the reaction mixture.

Scheme I, step c; A slurry of lithium aluminum hydride (350 mg, 9 mmol)and lithium iodide (1.16 g, 8.7 mmol) in toluene (34 mL) is cooled to-30° C. and treated with a solution of4-tert-butyldimethylsiloxy-3-cyclopentanone (3.509 g, 16.5 mmol),tert-butyl methyl ether (17 mL) and isopropanol (0.25 mL, 20 mol %)dropwise over 22 minutes. The temperature rises to -25° C. The reactionis then stirred for 2.5 hours at -20° C. to -25° C. Then saturatedammonium chloride (20 mL) is added to the reaction followed by water (5mL). The reaction is warmed to room temperature and then filtered. Thesolids are rinsed with toluene (20 mL). The phases of the filtrate areseparated. The aqueous phase is extracted with toluene (20 mL). Theorganic phases are combined, dried over anhydrous magnesium sulfate,filtered and concentrated under vacuum. The residue is purified byKugelrohr distillation (0.4 mmHg/60°-75° C.) to provide a colorless oil(2.17 g, 61%); cis/trans/l-2+l-4 addition, 95.9/3.1/1.

EXAMPLE 4

Preparation of cis-2-cyclopentenyl-1,4-diol. ##STR27##

Scheme I, step d; A solution ofcis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (50 g, 0.233 mol) intetrahydrofuran (250 mL) at room temperature is treated sequentiallywith triethylamine (5.00 mL, 0.036 mol) and tetrabutylammonium fluoride(250 mL of a 1.0N solution in tetrahydrofuran, 0.250 mol). The reactionis stirred for 3 hours and then concentrated under vacuum (40° C., 20mmHg). The residue is then purified by chromatography (silica gel,100×160 mm, 10% acetone/ethyl acetate) followed by recrystallizationfrom chloroform to provide the title compound (18.0 g, 77%) as whiteneedles; mp 57°-58° C., R_(f) =0.25 (10% acetone/ethyl acetate); ¹ H NMR(CDCl₃) δ 6.01 (s, 2 H), 4.62-4.68 (m, 1 H), 4.02 (d, J=7.3 Hz, 1 H),2.73 (dt, J=14.6, 7.3 Hz, 1 H), 1.57 (dt, J=14.5, 3.4 Hz, 1 H); ¹³ C NMR(CDCl₃) δ 136.3, 74.9, 43.3; IR (KBr) ν_(max) 3402, 3391, 3364 cm⁻¹ ; MS(CI) m/e (% relative intensity) 83 (M⁺ +H--H₂ O, 100).

Anal. Calcd for C₅ H₈ O₂ : C, 59.98; H, 8.05; Found: C, 59.79; H, 8.36.

EXAMPLE 5

Preparation of 4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enone. ##STR28##

Scheme I, step b; A solution of 4-hydroxy-2-cyclopentenone (1.41 g, 14.4mmol) in tetrahydrofuran (24 mL) is treated with 3,4-dihydro-2H-pyran (2mL) and pyridinium p-toluenesulfonate (500 mg, PPTS). The reaction isstirred at room temperature for 18 hours. The reaction mixture is thendiluted with ethyl acetate (25 mL) and washed with 50% saturated brine(2×30 mL). The organic layer is dried over anhydrous magnesium sulfate,filtered and concentrated under vacuum. The resulting crude brown oil ispurified by filtration through a plug of silica gel (25 g, 33% ethylacetate/hexane) to provide the title compound as a yellow oil (2.00 g,76%); ¹ H NMR (CDCl₃) δ 7.46 (2×dd, 1 H, J=16.3, 5.7 Hz), 6.2 (m, 1H),4.9 (m, 1 H), 4.80 (d appt, 1 H, J=23.8, 2.9 Hz), 3.9 (m, 1 H), 3.6 (m,1 H), 2.73 (2×dd, 1 H, J=18.4, 6.2 Hz), 2.35 (2×d, 1 H, J=18.4 Hz), 1.8(m, 1 H), 1.6 (m, 4 H); IR (neat) ν_(max) 2944, 2870, 2855, 1723, 1348,1202, 1182, 1152, 1128, 1078, 1032 cm⁻¹ ; MS (CI) m/e (% relativeintensity) 183 (M+H⁺, 28), 85(100).

EXAMPLE 6

Preparation of cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enol.##STR29##

Scheme I, step c; A slurry of lithium aluminum hydride (222 mg, 5.8mnmol), lithium iodide (3.2 g, 24 mmol), tert-butyl methyl ether (6 mL)and toluene (16 mL) is cooled to -15° C. A solution of4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enone (2.179 g, 11.97 mnmol,prepared in example 5) in tert-butyl methyl ether (2 mL) and toluene (2mL) is added dropwise over 40 minutes. The reaction mixture is allowedto stir for 30 minutes. Then sodium hydroxide (1N, 5 mL) is added slowlyto the reaction mixture. The slurry is filtered and the resulting phasesseparated. The aqueous phase is extracted with ethyl acetate (2×10 mL).The organic extracts are combined with the organic phase, dried overmagnesium sulfate, filtered and concentrated under vacuum. The crude oilis then purified by chromatography (silica gel, 30 g, 50% ethylacetate/hexane, 400 mL) to provide the title compound (1.62 g, 73%),cis/trans/l-2+l-4 addition, 88/8/4; ¹ H NMR (CDCl₃) δ 6.1 (m, 1 H), 4.7(m, 1 H), 4.6 (m, 2 H), 3.9 (m, 1 H), 3.5 (m, 1 H), 2 .7 (m, 1 H),1.4-2.0 (m, 8 H) ¹³ C NMR (CDCl₃) δ 137.2,137.1, 134.8, 133.6, 98.3,97.8, 79.7, 79.5, 74.7, 74.5, 62.6, 62.5, 42.0, 41.1, 31.1, 30.9, 25.4,19.6, 19.5; IR (neat) ν_(max) 2944, 2870, 2855, 1723, 1348, 1202, 1182,1152, 1128, 1078, 1032 cm⁻¹ ; MS (CI) m/e (% relative intensity) 183(M+H⁺, 7), 167 (M+H⁺ --H₂ O, 40), 85(100).

EXAMPLE 7

Preparation of cis-2-cyclopentenyl-1,4-diol.

Scheme I, step d; A solution ofcis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enol (338 mg, prepared inexample 6) in ethanol (4 mL) is treated with p-toluenesulfonic acidmonohydrate (38 mg, p-TsOH.H₂ O). The reaction is stirred at roomtemperature for 2 hours. Potassium carbonate (116 mg) is added and thereaction mixture is diluted with 25% hexane/ethyl acetate (10 mL). Thissolution is poured onto a plug of silica gel (10 g) and eluted with 25%hexane/ethyl acetate (3×30 mL) and ethyl acetate (2×40 mL) to providethe title compound (167 mg, 90%), cis/trans/l-2+l-4 addition, 88/8/4.

EXAMPLE 8

Preparation of 4-tert-butoxy-cyclopent-2-enone. ##STR30##

Scheme I, step b; A solution of 4-hydroxy-2-cyclopentenone (1.15 g, 11.7mmol) in methylene chloride is cooled to 3° C. and treated sequentiallywith tert-butyl trichloroacetimidate (4.2 mL, 23.7 mmol) and borontrifluoride diethyl etherate (0.15 mL). The reaction mixture is stirredat 3°-10° C. for 2 hours and then allowed to warm to room temperatureand stirred for 22 hours. The reaction mixture is then treated withsodium bicarbonate (250 mg) and filtered. The filtrate is concentratedunder vacuum and the residue is purified by chromatography (silica gel,39 g, 20% ethyl acetate/hexane, 600 mL) to provide the title compound(355 mg, 40%) as a yellow oil; ¹ H NMR (CDCl₃) δ 7.44 (dd, 1 H, J=18Hz), 6.2 (d, 1 H, J=5.4 Hz), 4.8 (m, 1 H), 2.68 (dd, 1 H, J=5.8, 18 Hz),2.25 (d, 1 H, J=18 Hz), 1.27 (s, 9 H); IR (neat) ν_(max) 2976, 2936,1721, 1368, 1352, 1188, 1103, 1161 cm⁻¹ ; MS (CI) m/e (% relativeintensity) 155 (M+H⁺, 22), 99 (100).

EXAMPLE 9

Preparation of cis-4-tert-butyloxy-cyclopent-2-enol. ##STR31##

Scheme I, step C; A slurry of lithium aluminum hydride (55 mg, 1.44mmol), lithium iodide (1.65 g, 5.76 mmol), tert-butyl methyl ether (2mL) and toluene (3 mL) is cooled to -15° C. The slurry is treateddropwise with 4-tert-butoxy-cyclopent-2-enone(430 mg, 2.79 mmol,dissolved in 1 mL of toluene) over 5 minutes. The reaction mixture isstirred at -20° C. to -12° C. for 2 hours and then allowed to warm toroom temperature and is stirred for 30 minutes. The reaction mixture isthen treated sequentially with sodium hydroxide (1N, 1 mL), thentert-butyl methyl ether (10 mL) and filtered. The phases of the filtrateare separated and the aqueous phase is extracted with tert-butyl methylether (15 mL). The organic extracts and organic phase is combined, driedover magnesium sulfate, filtered and concentrated under vacuum. Theresidue is purified by chromatography (silica gel, 30 g, 33% ethylacetate/hexane) to provide the title compound (183 mg, 42%) as a yellowoil, cis/trans/l-2+l-4 addition, 87/9.8/3.2; ¹ H NMR (CDCl₃) δ 5.9 (m, 1H), 5.8 (m, 1 H), 4.6 (m, 1 H), 4.5 (m, 1 H), 2.7 (m, 1 H), 2.0 (d,1 H,J=9.6 Hz), 1.5 (d appt, 1 H, J=4.5, 14 Hz), 1.2 (s, 9 H); ¹³ C NMR(CDCl₃) δ 136.6, 136, 75.5, 74.4, 74, 44.6, 28.7; ν_(max) 3395, 2974,2938, 2907, 2878, 1389, 1364, 1117, 1169, 1022 cm⁻¹ ; MS (CI) m/e (%relative intensity) 157 (M+H⁺ --H₂ O), 57, 83 (100).

EXAMPLE 10

Preparation of (-)-cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (A)and (-)-acetic acid 4-tert-butyldimethylsilyloxy-cyclopent-2-enyl ester(B). ##STR32##

Scheme II, step A; Cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol(10.0 g, 46.6 mmol, prepared in example 3a) is dissolved in tert-butylmethyl ether (60 mL, anhydrous). To the solution is added triethylamine(4.5 mL, 32.3 mmol), pancreatin (30 g, available from Sigma ChemicalCompany), and vinyl acetate (22 mL, 239 mmol). The reaction is allowedto stir for 7 hours at room temperature. The reaction is then filteredthrough diatomaceous earth and the filtrate is concentrated undervacuum. The products are separated by chromatography on silica gel (5%to 20% ethyl acetate/hexane) to provide (-)-acetic acid4-tert-butyldimethylsilyloxy-cyclopent-2-enyl ester (B. 6.1 g, 51%yield, 99% ee), α!_(D) -0.2°, (c=0.52, chloroform) as a yellow oil and(-)-cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (A, 4.7 g, 47%yield, >99% ee), α!_(D) -18.6°, (c=1.01, chloroform) as a yellow oil.

EXAMPLE 11

Preparation of (-)-cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enol (A)and (-)-acetic acid cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enylester (B). ##STR33##

Scheme II, step A; Cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enol(1.091 g, 5.92 mmol, prepared in example 6) is dissolved in tert-butylmethyl ether (8.6 mL, anhydrous). To the solution is added triethylamine(0.59 mL, 4.2 mmol), pancreatin (3.2 g, available from Sigma ChemicalCompany), and vinyl acetate (2.7 mL, 29 mmol). The reaction is allowedto stir for 7 hours at room temperature. The reaction is then filteredthrough diatomaceous earth and the filtrate is concentrated undervacuum. The products are separated by chromatography on silica gel (10%to 20% ethyl acetate/hexane) to provide (-)-acetic acidcis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enyl ester (B, 601 mg, 45%yield, 91% ee), α!_(D) =-19.8°, (c=1.00, chloroform) as a yellow oil and(-)-cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enol (A, 560 mg, 50%yield, 94% ee), α!_(D) =-9.9°, (c=1.06, chloroform) as a yellow oil.

(-)-cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enol

Anal. Calcd for C₁₁ H₁₆ O₃.0.13 H₂ O: C, 64.38; H, 8.78; Found: C,64.32; H, 8.97.

(-)-acetic acid cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enyl ester

Anal. Calcd for C₁₂ H₁₈ O₄ : C, 63.70; H, 8.01; Found: C, 63.42; H,8.09.

EXAMPLE 12

Preparation of (+)-cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol.##STR34##

Scheme II, step B; Dissolve (-)-acetic acid4-tert-butyldimethylsilyloxy-cyclopent-2-enyl ester (2.3 mmol, preparedin example 10) in THF/methanol/water (2.7/0.9/0.9 mL). Add lithiumhydroxide monohydrate (2.5 mmol) with stirring. After stirring for about3 hours at room temperature, dilute the reaction with water (10 mL) andextract with tert-butyl methyl ether. Combine the organic phases, dryover anhydrous magnesium sulfate, filter and concentrate under vacuum.Purify the residue by flash chromatography (silica gel, 20% ethylacetate/hexane) to provide the title compound (452 mg, 92% yield), α!²⁰_(D) =+21.80, (c=1.02, chloroform).

EXAMPLE 13

Preparation of (+)-cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enol.##STR35##

Scheme II, step B; Dissolve (-)-acetic acidcis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enyl ester (106 mg, 0.47mmol, prepared in example 11) in THF/methanol/water (1.5/0.5/0.5 mL).Add lithium hydroxide monohydrate (0.57 mmol) with stirring. Afterstirring for about 3 hours at room temperature, dilute the reaction withtert-butyl methyl ether (10 mL) and water (10 mL). Extract withtert-butyl methyl ether (2×10 mL). Combine the organic extracts, dryover anhydrous magnesium sulfate, filter and concentrate under vacuum.Purify the residue by flash chromatography (silica gel, 2.5 g, 1.7×2.5cm column, 50% ethyl acetate/hexane, 150 mL) to provide the titlecompound (80 mg, 93% yield), α!²⁰ _(D) =+9.9°, (c=0.98, chloroform).

EXAMPLE 14

Preparation of (-)-cis-4-tert-butyloxy-cyclopent-2-enol (A) and(-)-acetic acid cis-4-tert-butyloxy-cyclopent-2-enyl ester-(B).##STR36##

Scheme II, step A; Cis-4-tert-butyloxy-cyclopent-2-enol (485 mg, 3.1mmol, prepared in example 9) is dissolved in tert-butyl methyl ether(8.6 mL, anhydrous). To the solution is added triethylamine (0.7 eq),pancreatin (3 wt eq, available from Sigma Chemical Company), and vinylacetate (5 eq). The reaction is allowed to stir for 17 hours at roomtemperature. The reaction is then filtered through diatomaceous earthand the filtrate is concentrated under vacuum. The products areseparated by chromatography on silica gel (10% to 20% ethylacetate/hexane) to provide (-)-acetic acidcis-4-tert-butyloxy-cyclopent-2-enyl ester (B, 50% yield, 76% ee),α!_(D) =-10.90, (c=0.98, chloroform), ¹ H NMR (CDCl₃) δ 5.94 (d, 1 H,J=5.5 Hz), 5.89 (d, 1 H, J=5.5 Hz), 5.46 (appt, 1 H, J=5.5 Hz), 4.52(appt, 1 H, J=5.5 Hz), 2.8 (m, 1 H), 2.0 (s, 3 H), 1.6 (d appt, 1 H,J=4.8, 14 Hz), 1.22 (s, 9 H); ¹³ C NMR (CDCl₃) δ 171.2, 138.6, 131.6,77.4, 77.2, 41, 28.7, 28.6, 21.4; IR (neat) ν_(max) 2976, 1738, 1364,1242, 1196, 1067, 1020 cm⁻¹ ; CIMS m/e (% relative intensity) 199 (M+H⁺,4), 139 (M+H⁺ --AcOH, 70), 83 (100), and(-)-cis-4-tert-butyloxy-cyclopent-2-enol (A, 194 mg, 40% yield, >98%ee), α!_(D) =-17.2°, (c=1.09, chloroform) as a yellow oil.

(-)-cis-4-tert-butyloxy-cyclopent-2-enol

Anal. Calcd for C₉ H₁₆ O₂ : C, 69.19; H, 10.32; Found: C, 69.07; H,10.37.

(-)-acetic acid cis-4-tert-butyloxy-cyclopent-2-enyl ester

Anal. Calcd for C₁₁ H₁₈ O₃ : C, 66.64; H, 9.15; Found: C, 67.11; H,9.03.

EXAMPLE 15

Preparation of (+)-cis-4-tert-butyloxy-cyclopent-2-enol. ##STR37##

Scheme II, step B; Dissolve (-)-acetic acidcis-4-tert-butyloxy-cyclopent-2-enyl ester (90 mg, 0.45 mmol, preparedin example 14) in THF/methanol/water (1.5/0.5/0.5 mL). Add lithiumhydroxide monohydrate (23.7 mg) with stirring. After stirring for about2 hours at room temperature, dilute the reaction with water (10 mL) andextract with tert-butyl methyl ether. Combine the organic phases, dryover anhydrous magnesium sulfate, filter and concentrate under vacuum.Purify the residue by flash chromatography (silica gel, 2 g, 40% diethylether/hexane, 1.5×2.5 cm column) to provide the title compound (71 mg,quantitative yield, 76% ee) as a pale yellow oil, α!²⁰ _(D) =+14.6°, (c1.03, chloroform).

EXAMPLE 16

Preparation of cis-4-benzyloxy-cyclopent-2-enol ##STR38##

Scheme I, step b; In a manner analogous to the procedure described inexample 8, 4-benzyloxy-2-cyclopent-2-enone is prepared from4-hydroxy-2-cyclopentenone, benzyl trichloroacetimidate and borontrifluoride diethyl etherate.

Scheme I, step c; A solution of lithium aluminum hydride (45 mg, 1.2mmol) and lithium iodide (451 mg, 3.37 mmol) in diethyl ether (4 mL) iscooled to -30° C. and treated dropwise over 5 minutes with a solution of4-benzyloxy-2-20 cyclopent-2-enone (444 mg, 2.36 mmol, prepared above)in diethyl ether (1 mL). The reaction mixture is stirred for 1.5 hoursat -25° C. and then treated with 1N sodium hydroxide (1 mL). Thereaction mixture is then allowed to warm to room temperature and isfiltered. The filtrate is extracted with ethyl acetate (2×10 mL). Theorganic phase is dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum. The residue is purified by chromatography toprovide the title compound (151 mg, 34% yield) as a pale yellow oil,28/4/3, cis/trans/1,4+1,2; ¹ H NMR (CDCl₃) δ 7.3 (m, 5 H), 6.05 (appt, 2H, J=7 Hz), 4.6 (m, 1 H), 4,56 (dd, 2 H, J=11.7, 17 Hz), 4.44 (dd, 1 H,J=4, 6.8 Hz), 2.7 (m, 1 H), 1.67 (d appt, 1 H, J=4, 14 Hz); ¹³ C NMR(CDCl₃) δ 138.6, 137.4, 134.5, 128.7, 128.1, 127.9, 81.7, 75.3, 71.3,41.3; IR (neat) ν_(max) 3381, 2918, 2851, 1360, 1072, 1051, 1028 cm⁻¹ ;CIMS m/e (% relative intensity) 173 (M+H⁺ --H₂ O), 91 (100).

Anal. Calcd for C₁₂ H₁₄ O₂ : C, 75.77; H, 7.41; Found: C, 75.61; H,7.78.

EXAMPLE 17

Preparation of (-)-cis-4-benzyloxy-cyclopent-2-enol (A) and (-)-aceticacid cis-4-benzyloxy-cyclopent-2-enyl ester (B). ##STR39##

Scheme II, step A; Cis-4-benzyloxy-cyclopent-2-enol (500 mg, prepared inexample 16) is dissolved in tert-butyl methyl ether (8.6 mL, anhydrous).To the solution is added triethylamine (0.7 eq), pancreatin (3 wt eq,available from Sigma Chemical Company), and vinyl acetate (5 eq). Thereaction is allowed to stir for 7 hours at room temperature. Thereaction is then filtered through diatomaceous earth and the filtrate isconcentrated under vacuum. The products are separated by chromatographyon silica gel (20% ethyl acetate/hexane) to provide(-)-cis-4-benzyloxy-cyclopent-2-enol (A) (147 mg, 29% yield) α!²⁰ _(D)--12°, (c=1.09, chloroform), and (-)-acetic acidcis-4-benzyloxy-cyclopent-2-enyl ester (B) (427 mg, 70% yield), α!²⁰_(D) =-5.2°, (c=0.97, chloroform), ¹ H NMR (CDCl₃) δ 7.3 (m, 5 H), 6.13(d, 1 H, J=5 Hz), 5.99 (d, 1 H, J=5 Hz), 5.5 (m, 1 H), 4.59 (d, 1 H,J=11.8 Hz), 4.54 (d, 1 H, J=11.8 Hz), 4.5 (m, 1 H), 2.78 (d appt, 1 H,J=7.2, 14.3 Hz), 2.05 (s, 3 H) , 1.76 (d appt, 1 H, J=4.4, 14.3 Hz); ¹³C NMR (CDCl₃) δ 171.1, 138.5, 136.4, 133.1, 128.7, 128, 127.9, 81.4,77.1, 71.2, 37.8, 21.4.

EXAMPLE 18

Preparation of (+)-cis-4-benzyloxy-cyclopent-2-enol. ##STR40##

Scheme II, step B; Dissolve (-)-acetic acidcis-4-benzyloxy-cyclopent-2-enyl ester (158 mg, 0.68 mmol, prepared inexample 17) in THF/methanol/water (1.5/0.5/0.5 mL). Add lithiumhydroxide monohydrate (0.75 mmol) with stirring. After stirring forabout 2 hours at room temperature, dilute the reaction with water (10mL) and extract with tert-butyl methyl ether. Combine the organicphases, dry over anhydrous magnesium sulfate, filter and concentrateunder vacuum. Purify the residue by flash chromatography (silica gel, 2g, 20% ethyl acetate/hexane, 1.5×2.5 cm column) to provide the titlecompound (120 mg, 92% yield), α!²⁰ _(D) =+5.0°, (c=0.93, chloroform).

EXAMPLE 19

Preparation of (-)-cis-4-acetoxy-cyclopent-2-enol. ##STR41##

Scheme II, step B; Dissolve (-)-acetic acidcis-4-tert-butyldimethylsilyloxy-cyclopent-2-enyl ester (11.53 g, 45mmol, prepared in example 10) in tetrahydrofuran (49.5 mL) andtriethylamine (0.7 mL). Treat the solution with a solution oftetra-n-butylammonium fluoride (49.5 mL of a 1M solution in THF, 49.5mmol) and stir for 2 hours at room temperature. Then concentrate thereaction under vacuum and purify the residue by chromatography (silicagel, 33% to 50% ethyl acetate/hexane) to provide a white solid (5.85 g)which is recrystallized from tert-butyl methyl ether/heptane (80 mL/ 100mL) to provide the title compound (4.99 g, 78% yield, >98% ee), α!²⁰_(D) =-68°, (c=0.98, chloroform), mp 48-49° C.; ¹ H NMR (CDCl₃) δ6.12-6.14 (m, 1 H), 5.99-6.01 (m, 1 H), 5.49-5.54 (m, 1 H), 4.70-4.77(m, 1 H), 2.83 (dt, 1 H, J=14.5, 7.3 Hz), 2.22 (d, 1 H, J=7.8 Hz), 2.08(s, 3 H), 1.6 (dt, 1 H, J=14.5, 3.8 Hz).

EXAMPLE 20

Preparation of (+)-acetic acidcis-4-tert-butyldimethylsilyloxy-cyclopent-2-enyl ester. ##STR42##

Dissolve (-)-cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (1 9, 4.67mmol, prepared in example 10) in pyridine (20 mL) and treat with aceticanhydride (2 mL). Stir the reaction overnight. Dilute the reaction withdiethyl ether (100 mL), wash with 3M hydrochloric acid (3×100 mL),saturated sodium bicarbonate (100 mL), brine (100 mL), dry overanhydrous magnesium sulfate, filter and concentrate under vacuum toprovide the title compound (1 g, 98% yield), R_(f) =0.5 (5% ethylacetate/hexane), α!²⁰ _(D) =+1.3°, (c=1.00, chloroform), ¹ H NMR (CDCl₃)δ 5.9 (m, 1 H), 5.5 (m, 1 H), 4.7 (m, 1 H), 2.8 (m, 1 H), 2.05 (s, 3 H),1.6 (m, 1 H), 0.91 (s, 9 H), 0.09 (s, 6 H); ¹³ C NMR (CDCl₃) δ 170.8,138.8, 131.1, 76.9, 74.8, 41.1, 25.8, 21.1, 18.1, -4.7, -4.6; IR (neat)ν_(max) 2955, 2932, 2859, 1739, 1369, 1240, 1105, 1062, 1049 cm⁻¹ ; CIMSm/e (% relative intensity) 256 (M+H⁺, 7), 197 (M+H⁺ --AcOH, 100).

Anal. Calcd for C₁₃ H₂₄ O₃ Si; C, 60.90; H, 9.43; Found: C, 60.89; H,9.67.

EXAMPLE 21

Preparation of (+)-acetic acidcis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enyl ester (B). ##STR43##

Dissolve (-)-cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enol (292 mg,1.59 mmol, prepared in example 11) in pyridine (2.8 mL) and treat withacetic anhydride (0.39 mL) and dimethylaminopyridine (16 mg). Stir thereaction overnight. Concentrate the reaction under vacuum, dissolve theresidue with ethyl acetate (10 mL). Wash with 0.5M hydrochloric acidthat is 1/2 saturated with brine (2×10 mL), saturated sodium bicarbonate(10 mL), brine (10 mL), dry over anhydrous magnesium sulfate, filter andconcentrate under vacuum. Purify the residue by chromatography (silicagel, 10 g, 1.5×4 cm column, 20% ethyl acetate/hexane) to provide thetitle compound (290 mg, 81%).

EXAMPLE 22

Preparation of (-)-cis-4-acetoxy-cyclopent-2-enol. ##STR44##

Dissolve (-)-acetic acidcis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enyl ester (192 mg, 0.85mmol, prepared in example 11) in ethanol (1.5 mL) and treat withp-toluenesulfonic acid (11.7 mg). Stir the reaction at room temperaturefor 2 hours. Add carbonate or bicarbonate to neutralize the reactionmixture and concentrate under vacuum. Purify the residue bychromatography (silica gel, 3 g, 1.5×3 cm column, 33% ethylacetate/hexane, 80 mL), to provide the title compound (90 mg, 75% yield,91% ee), α!²⁰ _(D) =-66.1°, (c=0.63, chloroform).

EXAMPLE 23

Preparation of (-)-cis-3-acetoxy-cyclopentanol. ##STR45##

Dissolve (-)-cis-4-acetoxy-cyclopent-2-enol (11.0 g, 77.4 mmol, preparedin example 19) in ethanol (50 mL) and treat with Raney nickel (1.1 g,previously washed with water (2×50 mL) and ethanol (2×50 mL), Ra--Ni).Charge the atmosphere with hydrogen at 50 psi (344.74 kPa) and shake themixture. After 20 minutes, filter the solution and treat the filtratewith triethylamine (1.0 mL, 7.2 mmol). After one hour concentrate thesolution under vacuum and distill the residue by Kugelrohr distillation(60°-80° C., 1 mm Hg), to provide the title compound (9.74 g, 87%) as acolorless oil.

EXAMPLE 24

Preparation of (1S,3R)-acetic acid 3-methanesulfonyloxy-cyclopentylester. ##STR46##

Dissolve (1S,3R)-cis-3-acetoxy-cyclopentanol (9.75 g, 67.6 mmol,prepared in example 23) in tert-butyl methyl ether (80 mL, anhydrous)and cool to -8° C. with stirring. Add methanesulfonyl chloride (5.7 mL,73.6 mmol, mesyl chloride) over 5 minutes, followed by dropwise additionof triethylamine (11.4 mL, 81.2 mL), over about 30 minutes, maintainingthe temperature below -2° C. The ice bath is then removed and themixture is stirred for 2 hours. The mixture is poured into a water/brinemixture (50 mL/50 mL). The layers are separated and the aqueous layerextracted with tert-butyl methyl ether (100 mL). The organic layer andextract is combined, dried over anhydrous magnesium sulfate, filteredand concentrated under vacuum to provide the title compound (14.4 g) asa yellow oil; ¹ H NMR (CDCl₃) δ 8 5.1 (m, 2 H), 3.02 (s, 3 H), 2.41 (m,1 H), 2.05 (s, 3 H), 2.0 (m, 5 H).

EXAMPLE 25

Preparation of (-)-cis-3-tert-butyldimethylsilyloxy-cyclopentanol.##STR47##

Dissolve (-)-cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (28.85 g,135 mmol, prepared in example 10) in ethanol (75 mL) and treated withRaney nickel (1.85 g, 32 mmol, previously washed with water (2×50 mL)and ethanol (2×50 mL)). Charge the atmosphere with hydrogen at 50 psi(344.74 kPa) and shake the mixture. After 5.25 hours, filter thereaction. Cool the filtrate to 0° C. and treat with sodium borohydride(0.54 g, 14.3 mmol). After stirring for 2 hours, concentrate thesolution under vacuum and distill the resulting oil by Kugelrohrdistillation (40°-60° C., 1 mmHg) to provide the title compound (25.5 g,87%) as a colorless oil, α!²⁰ _(D) =-3.9°, (c=0.99, chloroform); ¹ H NMR(CDCl₃) δ 4.4 (m, 1 H), 4.3 (m, 1 H), 3.03 (d, 1 H, J=10.5 Hz), 1.9-1.6(m, 6 H), 0.89 (s, 9 H), 0.07 (s, 6 H); ¹³ C NMR (CDCl₃) δ 74.9, 74.1,44.4, 34.2, 34.1, 25.8, 17.9, -4.9, -5.0; IR (neat) ν_(max) 3405, 2957,2932, 2888, 2858, 1256, 1091, 1069, 1038, 1026 cm⁻¹ ; CIMS m/e (%relative intensity) 217 (M+H⁺, 81), 199 (M+H⁺ --H₂ O, 37), 67 (100).This (-)-enantiomer (title compound) could not be separated from the(+)-enantiomer (antipode) using the previously described chiral column.

Anal. Calcd for C₁₁ H₂₄ O₂ Si: C, 61.06; H, 11.17; Found: C, 61.28; H,10.85.

The above reductions in examples 23 and 25 may also be effected usingsuch catalysts as platinum on Al₂ O₃, nickel boride, platinum on CaCO₃,Wilkinson's Catalyst ( C₆ H₅)₃ P!₃ RhCl) and the like.

EXAMPLE 26

Preparation of (1S,3R)-methanesulfonic acid3-tert-butyldimethylsilyloxy-cyclopentyl ester. ##STR48##

Dissolve (-)-cis-3-tert-butyldimethylsilyloxy-cyclopentanol (9.20 g,42.5 mmol) in anhydrous tert-butyl methyl ether (50 mL) and cool to -5°C. Treat the solution with methanesulfonyl chloride (3.6 g, 46.5 mmol,mesyl chloride), followed by triethylamine (7.2 mL, 51.7 mmol), at sucha rate as to keep the temperature between -5° C. and -2° C. with an icebath. The ice bath is removed and the solution is stirred for 2 hours.The mixture is then transferred to a separatory funnel and treated withbrine/water (50 mL/50 mL). The layers are separated and the aqueouslayer is extracted with tert-butyl methyl ether (2×50 mL). The organiclayer and extracts are combined, washed with brine, dried over anhydrousmagnesium sulfate, filtered and concentrated under vacuum to provide thetitle compound (12.1 g, 97% yield) as a colorless oil; ¹ H NMR (CDCl₃) δ5.1 (m, 1 H), 4.2 (m, 1 H), 2.99 (s, 3 H), 2.3 (m, 1 H), 2.0 (m, 3 H),1.8 (m, 2 H), 0.88 (s, 9 H), 0.05 (s, 6 H).

EXAMPLE 27

Preparation of 4-trityloxy-2-cyclopentenone. ##STR49##

Scheme I, step b; A solution of trityl chloride (3.44 g, 12.3 mmol) inmethylene chloride (20 mL) is treated sequentially with 1,8-diazabicyclo5.4.0!undec-7-ene (2.2 mL, 14.7 mmol, DBU) and4-hydroxy-2-cyclopentenone (1.01 g, 10.0 mmol, in 5 mL of methylenechloride, prepared in example 1). The reaction is stirred for 3 days atroom temperature and then poured onto ice (approximately 25 mL). Thephases are separated and the organic phase is washed with water (25 mL).The organic phase is dried over anhydrous magnesium sulfate, filteredand concentrated under vacuum. The residue is purified by columnchromatography (silica gel, 10-20% ethyl acetate/hexane) to provide thetitle compound (1.26 g, 36 %) as a pale yellow oil; ¹ H NMR (CDCl₃) δ7.5 (m, 6 H), 7.3 (m, 9 H), 6.85 (dd, 1 H), 6.05 (d, 1 H), 4.8 (m, 1 H),2.1 (m, 2 H); ¹³ C NMR (CDCl₃) δ 206.6, 162.9, 144.3, 135.2, 128.8,128.4, 127.7, 88.2, 73.1, 43.4; IR (KBr) ν_(max) 3061, 1719, 1491, 1449,1352, 1181, 1107, 1053 cm⁻¹.

EXAMPLE 28

Preparation of (+/-)-cis-4-trityloxy-2-cyclopentenol. ##STR50##

Scheme I, step C; A slurry of 4-trityloxy-2-cyclopentenone (1.03 g, 3.03mmol, prepared in example 27) in toluene (8 mL) is cooled to -20° C. andtreated sequentially with lithium aluminum hydride (76 mg, 2.0 mL),lithium iodide (1.06 g, 7.9 mmol) and dropwise with tert-butyl methylether (2 mL, over 5 minutes). The reaction is stirred for 1 hour at -20°C., warmed to 0° C. over 30 minutes, and stirred at 0° C. to 15° C. for4 hours. The reaction is quenched by slow addition of 1N NaOH (2 mL) andthen the reaction is filtered. The solids are washed with tert-butylmethyl ether and the phases of the filtrate are separated. The organicphase is dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum. The residue is purified by columnchromatography (silica gel, 20% ethyl acetate/hexane) to provide thetitle compound as a white foam (980 mg, 95%). ¹ H NMR (CDCl₃) δ 7.5 (m,6 H), 7.3 (m, 9 H), 5.79 (d, 1 H), 5.14 (d, 1 H), 4.5 (m, 1 H), 4.4 (m,1 H), 2.2 (m, 1 H), 1.42 (d, 1 H); ¹³ C NMR (CDCl₃) δ 145.1, 136.2,135.9, 129.0, 128.1, 127.3, 87.7, 77.4, 74.9, 43.2; IR (KBr) ν_(max)3422, 3057, 1491, 1364, 1084, 1065, 1024 cm⁻¹. Example 28a

Preparation of cis-2-cyclopentenyl-1,4-diol. ##STR51##

A solution of (+/-)-cis-4-trityloxy-2-cyclopentenol (200 mg, 0.58 mmol,prepared in example 28) in ethanol (2 mL) is treated withp-toluenesulfonic acid (20 mg) and stirred at 55° C. for 8 hours. Thereaction mixture is then concentrated under vacuum (55° C./15 mmHg) andthe residue is purified by column chromatography (silica gel, 10%acetone/ethyl acetate) to provide the title compound (58 mg);cis/trans/l-2+l-4 addition, 30/1/trace.

EXAMPLE 29

Preparation of (+/-)-cis-3-tert-butyldimethylsilyloxycyclopentanol.##STR52##

Combine (+/-)-cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (2.50 g,11.6 mmol, prepared in example 3) and Ni₂ B (8.5 mL of a 0.14M slurry inmethanol, 10 mol %) in methanol (14 mL). Stir the slurry under anatmosphere of hydrogen for 18.5 hours. Then replace the hydrogenatmosphere with nitrogen, filter through diatomaceous earth and rinsethe solids with methanol (50 mL). Concentrate the filtrate under vacuum(15 mmHg/40° C.) and purify the residue by Kugelrohr distillation (0.6mmHg/60°-65° C.) to provide the title compound as a colorless oil (2.31g, 92%).

EXAMPLE 30

Preparation of (1S,3R)-(-)-cis-3-tert-butyldimethylsilyloxycyclopentanol(A) and (lR,3S)-(+)-cis-3-tert-butyldimethylsilyloxycyclopentanylacetate (B). ##STR53##

Scheme III, step A; Combine(+/-)-cis-3-tert-butyldimethylsilyloxycyclopentanol (2.119 g, 9.8 mmol,prepared in example 29), pancreatin (6.2 g, 3 weight equivalents),triethylamine (0.9 mL, 6.5 mmol) and vinyl acetate (4.3 mL) intert-butyl methyl ether (12 mL) and stir for 27 hours at roomtemperature. Then filter the reaction through diatomaceous earth andconcentrate the filtrate under vacuum (room temperature/ 15 mmHg).Purify the residue by column chromatography silica gel, 55 g, hexane(300 mL) followed by 5% ethyl acetate/hexane (500 mL)! to provide the(lR,3S)-(+)-3-tert-butyldimethylsilyloxycyclopentanyl acetate (1.23 g,49% yield, 98% ee as determined from gas chromatography with a chiralcolumn) and (1S,3R)-(-)-3-tert-butyldimethylsilyloxycyclopentanol (771mg, 37% yield, 92% ee as determined from its acetate derivative followedby GC chiral column analysis, see example 30a).

Physical data for (lS,3R)-(-)-3-tert-butyldimethylsilyloxycyclopentanol;α!²⁰ _(D) =-3.7° (c=1.20, chloroform); ¹ H NMR (CDCl₃) δ 4.4 (m, 1 H),4.3 (m, 1 H), 3.03 (d, 1 H), 1.9-1.6 (m, 6 H), 0.89 (s, 9 H), 0.07 (s, 6H); ¹³ C NMR (CDCI₃) δ 74.9, 74.1, 44.4, 34.2, 34.1, 25.8, 17.9, -4.9,-5.0; IR (neat) ν_(max) 3405, 2957, 2932, 2888, 2858, 1256, 1091, 1069,1038, 1026 cm⁻¹.

Anal. calcd for C₁₁ H₂₄ O₂ Si: C, 61.06; H, 11.18; Found: C, 61.32; H,11.13.

Physical data for (1R,3S)-(+)-3-tert-butyldimethylsilyloxycyclopentanylacetate; α!²⁰ _(D) =+7.0° (c=1.12, chloroform).

Anal. calcd for C₁₃ H₂₆ O₃ Si: C, 60.42; H, 10.14; Found: C, 60.70; H,10.51.

EXAMPLE 30a

Preparation of (1S,3R)-(-)-cis-3-tert-butyldimethylsilyloxycyclopentanylacetate. ##STR54##

Combine (1S,3R)-(-)-cis-3-tert-butyldimethylsilyloxycyclopentanol (209mg, 2.5 mmol, prepared in example 30), pyridine (1 mL), acetic anhydride(0.1 mL) and DMAP (5 mg). Stir the reaction at room 15 temperature for15.5 hours. Then dilute the reaction with diethyl ether (10 mL) and washsequentially with 0.5M HCl 1/2 saturated with sodium chloride (2×10 mL),saturated sodium bicarbonate (10 mL) and brine (10 mL). Analysis of thefiltrate indicates 92% ee for the title compound. Dry the organic phaseover anhydrous magnesium sulfate, filter and concentrate under vacuum.

α!²⁰ _(D) =-6.60° (c=0.99, chloroform); ¹ H NMR (CDCl₃) δ 5.0 (m, 1 H),4.2 (m, 1 H), 2.2 (m, 1 H), 2.02 (s, 3 H), 1.9 (m, 1 H), 1.7 (m, 2 H),0.89 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3 H); ¹³ C NMR (CDCl₃) δ 171.3,75.0, 72.7, 42.3, 34.3, 30.5, 26.0, 21.5, 18.3, -4.5; IR (neat) ν_(max)2957, 2932, 2859, 1740, 1250, 1115, 1096, 1045 cm⁻¹.

What is claimed is:
 1. A process for the preparation of the CIScompounds of the formulas (IIb) and (IV): ##STR55## wherein Z is C₂ -C₄alkanoyl; and Pg is selected from the group consisting of benzyl,substituted benzyl, --CH₂ OCH₃, --CH₂ SCH₃, --CH₂ OCH₂ phenyl, --CH₂OCH₂ CH₂ OCH₃, --CH₂ OCH₂ CCl₃, --CH(OCH₂ CH₂ Cl)₂, --CH₂ OCH₂ CH₂Si(CH₃)₃, --CH(OC₂ H₅)CH₃, --C(OCH₃)(CH₃)₂, --CH(CH₃)OCH(CH₃)₂, --CH₂CCl₃, --C(CH₃)₃, --CH₂ CH═CH₂, --CH₂ CH═CHphenyl, --CH(phenyl)₂,tetrahydropyranyl, 4-methoxytetrahydropyranyl, 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl,tetrahydrofuranyl, tetrahydrothiofuranyl, and SiR₁ R₂ R₃, wherein R₁, R₂and R₃ are each independently C₁ -C₄ alkyl, phenyl, benzyl, substitutedphenyl or substituted benzyl, comprising;a) dissolving a compound of theformula (I) wherein Pg is defined as above, in a suitable organicsolvent; ##STR56## b) treating the solution with a suitable Lewis acidand a suitable reducing agent at a temperature of from about --100° C.to about 20° C. to yield the CIS compound of formula (II); ##STR57##wherein Pg is as defined above; c) treating the CIS compound of formula(II) with a suitable enzyme and an excess of a suitable acylating agentin a suitable solvent, to yield a mixture of compounds of the formulas(IIb) and (IV), as defined above; and d) separating the compound offormula (IIb) from the compound of formula (IV).
 2. A process accordingto claim 1 wherein the suitable acylating agent is vinyl acetate.
 3. Aprocess 'according to claim 2 wherein the suitable enzyme is pancreatin.4. A process according to claim 3 wherein the suitable solvent istert-butyl methyl ether.
 5. A process according to claim 3 wherein thesuitable solvent is cyclohexane.
 6. A process according to claim 1 forpreparing compounds of formula, further comprising, hydrolyzing thecompound of formula (IV) ##STR58## wherein Z is C₂ -C₄ alkanoyl; and Pgis selected from the group consisting of benzyl, substituted benzyl,--CH₂ OCH₃, --CH₂ SCH₃, --CH₂ OCH₂ phenyl, --CH₂ OCH₂ CH₂ OCH₃, --CH₂OCH₂ CCl₃, --CH(OCH₂ CH₂ Cl)₂, --CH₂ OCH₂ CH₂ Si(CH₃)₃, --CH(OC₂ H₅)CH₃,--C(OCH₃)(CH₃)₂, --CH(CH₃)OCH(CH₃)₂, CH₂ CCl₃, --C(CH₃)₃, --CH₂ CH═CH₂,--CH₂ CH═CHphenyl, --CH(phenyl)₂, --C(phenyl)₃, tetrahydropyranyl,4-methoxytetrahydropyranyl, 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl,tetrahydrofuranyl, tetrahydrothiofuranyl, and SiR₁ R₂ R₃, wherein R₁, R₂and R₃ are each independently C₁ -C₄ alkyl, phenyl, benzyl, substitutedphenyl or substituted benzyl.
 7. A process according to claims 1 or 6wherein a suitable alcohol is added to the reaction mixtureconcomitantly with or prior to treating the compound of formulas (I),(Ia) or (Ib) with the suitable reducing agent.
 8. A process according toclaim 7 wherein the suitable alcohol is tert-butyldimethylsilanol.
 9. Aprocess according to claim 7 wherein the suitable alcohol isisopropanol.
 10. A process for the preparation of the CIS compounds ofthe formulas (VIb) and (VII): ##STR59## wherein Z is C₂ -C₄ alkanoyl;and Pg is selected from the group consisting of benzyl, substitutedbenzyl, --CH₂ OCH₃, --CH₂ SCH₃, --CH₂ OCH₂ phenyl, --CH₂ OCH₂ CH₂ OCH₃,--CH₂ OCH₂ CCl₃, --CH(OCH₂ CH₂ Cl)₂, --CH₂ OCH₂ CH₂ Si(CH₃)₃, --CH(OC₂H₅)CH₃, --C(OCH₃)(CH₃)₂, --CH(CH₃)OCH(CH₃)₂, --CH₂ CCl₃, --C(CH₃)₃,--CH₂ CH═CH₂, --CH₂ CH═CHphenyl, --CH(phenyl)₂, tetrahydropyranyl,4-methoxytetrahydropyranyl, 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl,tetrahydrofuranyl, tetrahydrothiofuranyl, and SiR₁ R₂ R₃, wherein R₁, R₂and R₃ are each independently C₁ -C₄ alkyl, phenyl, benzyl, substitutedphenyl or substituted benzyl, comprising treating the CIS compound offormula (VI); ##STR60## wherein Pg is as defined above, with a suitableenzyme and an excess of a suitable acylating agent in a suitablesolvent, to yield a mixture of compounds of the formulas (VIb) and(VII), as defined above; andf) separating the compound of formula (VIb)from the compound of formula (VII).
 11. A process according to claim 10wherein the suitable acylating agent is vinyl acetate.
 12. A processaccording to claim 11 wherein the suitable enzyme is pancreatin.
 13. Aprocess according to claim 12 wherein the suitable solvent is tert-butylmethyl ether.